After his return from the second expedition to Egypt, Champollion was appointed to the chair of Egyptian history and archaeology at the Collège de France, a chair which had been specially created for him by a decree of Louis Philippe I dated to the 12th of March 1831. He only gave three lectures before his illness forced him to give up teaching. Exhausted by his labors during and after his scientific expedition to Egypt, Champollion died of an apoplectic attack (stroke) in Paris on the 4th of March 1832 at the age of 41. He is buried in Père Lachaise Cemetery. On his tomb is a simple obelisk erected by his wife, and a stone slab stating simply: Ici repose Jean-François Champollion, né à Figeac dept. du Lot le 23 décembre 1790, décédé à Paris le 4 mars 1832 (Here rests Jean-François Champollion, born at Figeac, Department of the Lot, on 23 December 1790, died at Paris on 4 March 1832).

It was around this time that Champollion met Rosine Blanc (1794–1871), whom he married in 1818, after four years of engagement. They had one daughter, Zoraïde Chéronnet-Champollion (1824–89). Rosine was the daughter of a well-to-do family of Grenoblean glovemakers. At first her father did not approve of the match, since Champollion was a mere assistant professor when they first met, but with his increasing reputation he eventually agreed. Originally Jacques-Joseph was opposed to his brother's marriage too, finding Rosine too dull-witted, and he did not attend the wedding, but later he grew fond of his sister in-law. Although a happy family man, especially adoring his daughter, Champollion was frequently away for months or even years at a time, as he was traveling to Paris, to Italy, and to Egypt and his family remained in Zoé and Jacques-Joseph's property in Vif, near Grenoble. While in Livorno, Champollion developed an infatuation with an Italian poet, Angelica Palli. She presented an ode to Champollion's work at a celebration in his honor, and the two exchanged letters over the period 1826–1829 revealing the poor state of Champollion's marriage, yet an affair never developed.

Towards the end of March 1801, Jean-François left Figeac for Grenoble, which he reached on the 27th of March, and where Jacques-Joseph lived in a two-room flat on the rue Neuve. Jacques-Joseph was then working as an assistant in the import-export company Chatel, Champollion and Rif, yet taught his brother to read, and supported his education. His brother also may have been part of the source of Champollion's interest in Egypt, since as a young man he wanted to join Napoleon's Egyptian expedition, and often regretted not being able to go.

Given the difficulty of the task of educating his brother while earning a living, Jacques-Joseph decided to send his younger brother to the well-regarded school of the Abbé Dussert in November 1802, where Champollion would stay until the summer of 1804. During this period, his gift for languages first became evident: he started out learning Latin and Greek, but quickly progressed to Hebrew and other Semitic languages such as Ethiopic, Arabic, Syriac and Chaldean. It was while a student here that he took up interest in Ancient Egypt, likely encouraged in this direction by Dussert and his brother, both orientalists.

From 1804, Champollion studied at a lycée in Grenoble, but hated its strict curriculum which only allowed him to study oriental languages one day per week, and he begged his brother to move him to a different school. Nonetheless, at the lycée he took up the study of Coptic, which would become his main linguistic interest for years to come and prove crucial in his approach to decipherment of the hieroglyphs. He had a chance to practice his Coptic when he met Dom Raphaël de Monachis, a former Coptic Christian monk and Arabic translator to Napoleon, who visited Grenoble in 1805. By 1806, Jean-Jacques was making preparations to bring his younger brother to Paris to study at the University. Jean-François had by then already developed a strong interest for Ancient Egypt, as he wrote in a letter to his parents dated to January 1806: "I want to make a profound and continuous study of this ancient nation. The enthusiasm brought me by the study of their monuments, their power and knowledge filling me with admiration, all of this will grow further as I acquire new notions. Of all the people that I prefer, I shall say that none is as important to my heart as the Egyptians." To continue his studies, Champollion wanted to go to Paris, Grenoble offering few possibilities for such specialized subjects as ancient languages. His brother thus stayed in Paris from August to September that same year, so as to seek his admission in a specialized school. Before leaving however Champollion presented, on the 1st of September 1807, his Essay on the Geographical Description of Egypt before the Conquest of Cambyses before the Academy of Grenoble whose members were so impressed that they admitted him to the Academy six months later.

Already in 1806, he wrote to his brother about his decision to become the one to decipher the Egyptian script:

Champollion's first declared his love for Pauline Berriat in 1807. Pauline was Zoé's sister and thus his sister in law. His love was not reciprocated and Champollion instead had an affair until circa 1809 with a married woman named Louise Deschamps. In 1811 Louise re-married and Pauline died in 1813.

In 1808, Champollion received a scare when French Archeologist Alex Andre Lenoir published the first of his four volumes on Nouvelles Explications des Hieroglyphes. making the young scholar fear that his budding work had already been surpassed. But he was relieved to find that Lenoir still operated under the assumption that the hieroglyphs were mystic symbols and not a literary system expressing language. This experience made him even more determined to be the first to decipher the language and he began dedicating himself even more to the study of Coptic, writing in 1809 to his brother: "I give myself up entirely to Coptic ... I wish to know Egyptian like my French, because on that language will be based my great work on the Egyptian papyri." That same year, he was appointed to his first academic post, in history and politics at the University of Grenoble.

In 1810, he returned to Grenoble to take up a seat as joint professor of Ancient History at the newly reopened Grenoble University. His salary as an assistant professor at Grenoble was fixed at 750 francs, a quarter of the salary received by full professors.

In 1811, Champollion was embroiled in controversy, as Étienne Marc Quatremère, like Champollion a student of Silvestre de Sacy, published his Mémoires géographiques et historiques sur l'Égypte ... sur quelques contrées voisines. Champollion saw himself forced to publish as a stand-alone paper the "Introduction" to his work in progress L'Egypte sous les pharaons ou recherches sur la géographie, la langue, les écritures et l'histoire de l'Egypte avant l'invasion de Cambyse (1814). Because of the similarities in the topic matter, and the fact that Champollion's work was published after Quatremère's, allegations arose that Champollion had plagiarized the work of Quatremère. Even Silvestre de Sacy, the mentor of both authors, considered the possibility, to Champollion's great chagrin.

Jacques's son, Aimé-Louis (1812–94), wrote a biography of the two brothers, and he and his sister Zoë Champollion, were both interviewed by Hermine Hartleben whose major biography of Champollion was published in 1906.

During the Napoleonic Wars, Champollion was a young bachelor and thus liable to compulsory military Service, which would have put him in great danger due to the extremely high mortality of Soldiers in Napoleon's armies. Through the assistance of his brother and the prefect of Grenoble Joseph Fourier, who was also an egyptologist, he successfully avoided the draft by arguing that his work on deciphering the Egyptian script was too important to interrupt. First skeptical of the Napoleonic regime, after the fall of Napoleon in 1813 and the institution of the royalist regime under Louis XVIII, Champollion came to consider the Napoleonic state the lesser of two evils. Anonymously he composed and circulated songs ridiculing and criticizing the royal regime – songs that became highly popular among the people of Grenoble. In 1815 Napoleon Bonaparte escaped from his exile on Elba and landed with an army at the Côte d'Azur and marched directly on Grenoble where he was received as a liberator. Here he met with Champollion, whose many requests for exemption from the draft he remembered, and he asked him how his important work was progressing. Champollion replied, that he had just finished his Coptic grammar and dictionary. Napoleon requested that he send the manuscripts to Paris for publication. His brother Jacques joined the Napoleonic cause, putting both of the brothers in danger at the end of the Hundred Days when Napoleon was finally defeated, Grenoble being the last city to resist the royalist advances. In spite of the risk to themselves, having been put under Royalist surveillance, the Champollion brothers nonetheless aided the Napoleonic general Drouet d'Erlon who had been sentenced to death for his participation in the Battle of Waterloo, giving him shelter and helping him escape to Munich. The brothers were condemned to internal exile in Figeac, and Champollion was removed from his university post in Grenoble and the faculty closed.

British polymath Thomas Young was one of the first to attempt decipherment of the Egyptian hieroglyphs, basing his own work on the investigations of Swedish diplomat Johan David Åkerblad. Young and Champollion first became aware of each other's work in 1814 when Champollion wrote to the Royal Society of which Young was the secretary, requesting better transcriptions of the Rosetta stone, to Young's irritation, arrogantly implying that he would be able to quickly decipher the script if he only had better copies. Young had at that time spent several months working unsuccessfully on the Rosetta text using Åkerblad's decipherments. In 1815, Young replied in the negative, arguing that the French transcriptions were equally good as the British ones, and added that "I do not doubt that the collective efforts of savants, such as M. Åkerblad and yourself, Monsieur, who have so much deepened the study of the Coptic language, might have already succeeded in giving a more perfect translation than my own, which is drawn almost entirely from a very laborious comparison of its different parts and with the Greek translation" This was the first Champollion had heard of Young's research, and realizing that he also had a competitor in London was not to Champollion's liking.

These errors were finally corrected later that year when Champollion correctly identified the hieratic script as being based on the hieroglyphic script, but used exclusively on papyrus, whereas the hieroglyphic script was used on stone, and demotic used by the people. Previously, it had been questioned whether the three scripts even represented the same language; and hieroglyphic had been considered a purely ideographic script, whereas hieratic and demotic were considered alphabetic. Young, in 1815, had been the first to suggest that the demotic was not alphabetic, but rather a mixture of "imitations of hieroglyphics" and "alphabetic" signs. Champollion on the other hand correctly considered the scripts to coincide almost entirely, being in essence different formal versions of the same script.

In 1817, Champollion read a review of his "Égypte sous les pharaons", published by an anonymous Englishman, which was largely favorable and encouraged Champollion to return to his former research. Champollion's biographers have suggested that the review was written by Young, who often published anonymously, but Robinson, who wrote biographies of both Young and Champollion, considers it unlikely, since Young elsewhere had been highly critical of that particular work. Soon Champollion returned to Grenoble to seek employment again at the university, which was in the process of reopening the faculty of Philosophy and Letters. He succeeded, obtaining a chair in history and geography, and used his time to visit the Egyptian collections in Italian museums. Nonetheless, most of his time in the following years was consumed by his teaching work.

This task was exactly what Champollion set out to accomplish in the Précis, and the entire framing of the argument was as a rebuttal to M. le docteur Young, and the translation in his 1819 article which Champollion brushed off as "a conjectural translation".

In 1820, Champollion embarked in earnest on the project of decipherment of hieroglyphic script, soon overshadowing the achievements of British polymath Thomas Young who had made the first advances in decipherment before 1819. In 1822, Champollion published his first breakthrough in the decipherment of the Rosetta hieroglyphs, showing that the Egyptian writing system was a combination of phonetic and ideographic signs – the first such script discovered. In 1824, he published a Précis in which he detailed a decipherment of the hieroglyphic script demonstrating the values of its phonetic and ideographic signs. In 1829 he traveled to Egypt where he was able to read many hieroglyphic texts that had never before been studied, and brought home a large body of new drawings of hieroglyphic inscriptions. Home again he was given a professorship in Egyptology, but only lectured a few times before his health, ruined by the hardships of the Egyptian journey, forced him to give up teaching. He died in Paris in 1832, 41 years old. His grammar of Ancient Egyptian was published posthumously.

Under the new Royalist regime, the Champollion brothers invested much of their time and efforts in establishing Lancaster schools, in an effort to provide the general population with education. This was considered a revolutionary undertaking by the Ultra-royalists, who did not believe that education should be made accessible for the lower classes. In 1821 Champollion even led an uprising, in which he and a band of Grenobleans stormed the citadel and hoisted the tricolore instead of the Bourbon Royalist flag. He was charged with treason and went into hiding, but was eventually pardoned.

After his groundbreaking discoveries in 1822, Champollion made the acquaintance of the Pierre Louis Jean Casimir Duc de Blacas, an antiquary who became his patron and managed to gain him the favor of the king. Thanks to this, in 1824, he traveled to Turin to inspect a collection of Egyptian materials assembled by Bernardino Drovetti, which King Charles X had purchased, cataloguing it. In Turin and Rome, he realized the necessity of seeing Egyptian monuments first hand and began to make plans for an expedition to Egypt collaborating with Tuscan scholars and the Archduke Leopold. In 1824, he became a correspondent of the Royal Institute of the Netherlands.

Building on his progress, Champollion now began to study other texts in addition to the Rosetta stone, studying a series of much older inscriptions from Abu Simbel. During 1823, he succeeded in identifying the names of pharaohs Ramesses and Thutmose written in cartouches in these ancient texts. With the help of a new acquaintance, the Duke de Blacas in 1824, Champollion finally published the Précis du système hiéroglyphique des anciens Égyptiens dedicated to and funded by King Louis XVIII. Here he presented the first correct translation of the hieroglyphs and the key to the Egyptian grammatical system.

The Précis, which comprised over 450 ancient Egyptian words and hieroglyphics groupings, cemented Champollion as having the main claim to the decipherment of the hieroglyphs. In 1825, his former Teacher and enemy Silvestre de Sacy reviewed his work positively stating that it was already well "beyond the need for confirmation". In the same year, Henry Salt put Champollion's decipherment to the test, successfully using it to read further inscriptions, he published a corroboration of Champollion's system, in which he also criticized Champollion for not acknowledging his dependence on Young's work.

Following his successes and after several months of negociations and talks by Jacques-Joseph while he was still in Italy, Champollion was finally appointed curator of the Egyptian collections of the Musée du Louvre in a decree of Charles X dated to the 15th May 1826. The two Champollion brothers organised the Egyptian collection in four rooms on the first floor of the south side of the Cour Carrée. The visitors entered this section of the Louvre via a first room devoted to the funerary world of the Egyptians, the second room presented artefacts relating to civilian life in Ancient Egypt, while the third and fourth rooms were devoted to more artefacts pertaining mortuary activities and divinities. To accompany these extensive works, Champollion organised the Egyptian collection methodologically into well-defined series and pushed his museologic work to the point of choosing the appearance of the stands and pedestals.

In 1827, Ippolito Rosellini, who had first met Champollion during his 1826 stay in Florence, went to Paris for a year in order to improve his knowledge of the method of Champollion's system of decipherment. The two philologists decided to organize an expedition to Egypt to confirm the validity of the discovery. Headed by Champollion and assisted by Rosellini, his first disciple and great friend, the mission was known as the Franco-Tuscan Expedition, and was made possible by the support of the grand-duke of Tuscany, Leopold II, and Charles X. Champollion and his second-in-command Rossellini were joined on the expedition by Charles Lenormant, representing the French government, and a team of eleven Frenchmen including the egyptologist and Artist Nestor L'Hote and Italians including the Artist Giuseppe Angelelli.

While examining texts in the tombs at Saqqara in October, Champollion realized that the hieroglyphic word for "hour" included the hieroglyph representing a star, which served no phonetic function in the word. He wrote in his journal that the star glyph was "the determinative of all divisions of time". Determinatives are an important part of the hieroglyphic writing system. Champollion probably struck upon the concept while in Egypt, as it had not appeared in the 1828 edition of the Précis. Champollion also saw the sphinx and lamented that the inscription on its chest was covered by more sand than they would be able to remove in a week. Arriving in Dendera on November 16, Champollion was excited to see the Zodiac that he had deciphered in Paris. Here he realized that the glyph that he had deciphered as autocrator and which convinced him that the inscription was of recent date was in fact not found on the monument itself – it had seemingly been invented by Jomard's copyist. Champollion nonetheless realized that the late date was still correct, based on other evidence. After a day at Dendera, the expedition continued on to Thebes.

The expedition arrived back in Cairo in late September 1829 where the expedition bought 10,000 francs worth of antiquities, a budget extended to them by minister Rochefoucauld. Arriving in Alexandria, they were notified that the French boat that would take them back was delayed, and they had to stay here two months until the sixth of December. On their return to Alexandria, the Khedive Muhammad Ali Pasha, offered the two obelisks standing at the entrance of Luxor Temple to France in 1829, but only one was transported to Paris, where it now stands on the Place de la Concorde. Champollion and the Pasha spoke often and on the Pasha's request Champollion wrote an outline of the history of Egypt. Here, Champollion had no choice but to challenge the short Biblical chronology arguing that Egyptian civilization had its origins at least 6000 years before Islam. The two also spoke about social reforms, Champollion championing education of the lower classes – a point on which the two did not agree.

Even though Champollion was appalled by the rampant looting of ancient artefacts and destruction of monuments, the expedition also contributed to the destruction. Most notably, while studying the Valley of the Kings, he damaged KV17, the tomb of Seti I, by removing a wall panel of 2.26 x 1.05 m in a corridor. English explorers attempted to dissuade the destruction of the tomb, but Champollion persisted, stating that he had the permission of the Muhammad Ali Pasha. Champollion also carved his name into a pillar at Karnak. In a letter to the Pasha recommended that tourism, excavation and trafficking of artefacts be strictly controlled. Champollion's suggestions may have led to Muhammad Ali's 1835 ordinance prohibiting all exports of antiquities and ordering the construction of a museum in which to house the ancient artifacts.

Certain portions of Champollion's works were edited by Jacques and published posthumously. His Grammar and Dictionary of Ancient Egyptian had been left almost finished and was published posthumously in 1838. Before his death, he had told his brother "Hold it carefully, I hope that it will be my calling card for posterity". It contained his entire theory and method, including classifications of signs and their decipherments, and also a grammar including how to write and conjugate nouns and verbs. But it was marred by the still tentative nature of many readings, and Champollion's conviction that the hieroglyphs could be read directly in Coptic, whereas in fact they represented a much older stage of the language which differs in many ways from Coptic.

Returning to Marseille on the Côte d'Azur, the members of the expedition had to spend a month in quarantine on the ship before being able to continue on towards Paris. The expedition led to a posthumously published extensive Monuments de l'Égypte et de la Nubie (1845).

Building on Champollion's grammar, his student Karl Richard Lepsius continued to develop the decipherment, realizing in contrast to Champollion that vowels were not written. Lepsius became the most important champion of Champollion's work. In 1866, the Decree of Canopus, discovered by Lepsius, was successfully deciphered using Champollion's method, cementing his reputation as the true decipherer of the hieroglyphs.

Figeac honors him with La place des Écritures, a monumental reproduction of the Rosetta Stone by American Artist Joseph Kosuth (pictured to the right). And a museum devoted to Jean-François Champollion was created in his birthplace at Figeac in Lot. It was inaugurated on 19 December 1986 in the presence of President François Mitterrand and Jean Leclant, Permanent Secretary of the Academy of Inscriptions and Letters. After two years of building work and extension, the museum re-opened in 2007. Besides Champollion's life and discoveries, the museum also recounts the history of writing. The whole façade is covered in pictograms, from the original ideograms of the whole world.

Champollion has also been portrayed in many films and documentaries: For Example, he was portrayed by Elliot Cowan in the 2005 BBC docudrama Egypt. In David Baldacci's thriller involving the CIA, Simple Genius, the character named "Champ Pollion" was derived from Champollion.

With his work on the Précis, Champollion realized that in order to advance further he needed more texts, and transcriptions of better quality. This caused him to spend the next years visiting collections and monuments in Italy, where he realized that many of the transcriptions from which he had been working had been inaccurate – hindering the decipherment; he made a point of making his own copies of as many texts as possible. During his time in Italy, he met the Pope, who congratulated him on having done a "great Service to the Church," by which he was referring to the counter arguments he had provided against the challengers to the Biblical chronology. Champollion was ambivalent, but the Pope's support helped him in his efforts to secure funds for an expedition.