Smetona was born on 10 August [O.S. 28 July] 1874 in the village of Užulėnis, Kovno Governorate, Russian Empire, to a family of farmers – former serfs of the Taujėnai Manor, which belonged to the Radziwiłł family. Researcher Kazimieras Gasparavičius has traced Smetona's patrilineal ancestry to Laurentijus who was born around 1695 and lived near Raguva. Smetona was the eighth of nine children. His parents were hardworking people who managed to double their inherited 5 hectares (12 acres). His father was literate and Smetona learned to read at home.

His father died in 1885 and, despite financial difficulties, a year later Smetona – the only of his siblings – was sent to the primary school in Taujėnai where instruction was in Russian. His mother hoped that Smetona would become a priest. After graduation in 1889, Smetona wanted to continue his education, but gymnasiums admitted pupils only up to the age of 12 and he was already 15 years old. Therefore, he was forced to study privately in Ukmergė in order to catch up and be able to pass examinations to enter the 4th class of gymnasium. In summer 1891, he attempted to gain admission to the Liepāja Gymnasium as his brother Motiejus worked in a factory in Liepāja. He was refused and instead applied to the Palanga Pre-Gymnasium, which had no age restrictions. Smetona was an exemplary student (one of the top two students) and received a tuition waiver. As a superintendent of a student dormitory, he also received free housing and was able to support himself by providing private lessons. Three other Future signatories of the Act of Independence of Lithuania attended the Pro-Gymnasium at the same time: Steponas Kairys, Jurgis Šaulys, and Kazimieras Steponas Šaulys. As Palanga was close to East Prussia, it was easier to obtain Lithuanian literature, which was banned by the Tsarist authorities. Smetona began reading Lithuanian periodicals and books, including a history of Lithuania by Maironis.

After graduation in 1893, according to his family's wishes, he passed his entrance examinations for the Samogitian Diocesan Seminary in Kaunas. However, he felt no great calling for priesthood and enrolled at the Jelgava Gymnasium in Latvia. This was a cultural hub of the Lithuanian National Revival and attracted many Future Leaders in Lithuanian culture and politics, including Juozas Tūbelis and Vladas Mironas who later became Smetona's political companions. In particular, Lithuanian language and culture was openly promoted by the Linguist, Jonas Jablonskis, Teacher of Greek, with whom Smetona developed a close professional relationship. Jablonskis visited Smetona's native village collecting data on Lithuanian dialects. Smetona met his Future wife, Sofija Chodakauskaitė, through Jablonskis who recommended him as tutor for her brother.

In fall 1896, the administration of the Jelgava Gymnasium forced the Lithuanian students to recite their prayers in Russian while Latvian and German students were allowed to use their native languages. Smetona and other students refused and were expelled. Most later agreed to pray in Russian and were re-admitted, but a handful who refused were prohibited from attending any other school. The students sent petitions to Pope Leo XIII and Ivan Delyanov, Minister of National Education. Smetona and two others, Jurgis Šlapelis (lt) and Petras Vaiciuška, managed to secure an audience with Delyanov who allowed the Lithuanians to pray in Latin and the expelled students to continue their education. Smetona did not return to Jelgava and finished up at Gymnasium No. 9 in Saint Petersburg.

Upon graduation in 1897, Smetona entered the Faculty of Law of the University of Saint Petersburg. He was more interested in history and languages, but knew that as a Catholic his choices were limited to priest, Lawyer, or Doctor if he wanted to work in Lithuania. Saint Petersburg, with a direct railway connection to Lithuania, was becoming a Lithuanian cultural center. Smetona joined and chaired a secret Lithuanian student organization; he was later succeeded by Steponas Kairys. He also joined a Lithuanian choir led by Česlovas Sasnauskas, organist at the Church of St. Catherine. Smetona was exposed to socialist ideas and even read Marx's Capital, but resolutely rejected them. He was expelled from the university, imprisoned for two weeks, and deported to Vilnius for participating in the February 1899 student protests. It was the first time Smetona visited the city, the historical capital of the Grand Duchy of Lithuania, and it left a deep impression on him. A month later, he was allowed to return to the university.

In 1898, Smetona and his roommate, Vladas Sirutavičius (lt), using a mimeograph printed about 100 copies of a brief Lithuanian grammar written by Petras Avižonis (lt) based on the German-language writings of Frydrichas Kuršaitis (lt). This grammar was insufficient for Lithuanian needs and in summer 1900 Jonas Jablonskis set out to work on his Lithuanian grammar. He was assisted by Avižonis, Žemaitė, and Smetona, though Smetona mostly edited works of Bishop Motiejus Valančius. The grammar was published in 1901 and became a fundamental work in establishing the standard Lithuanian language. In early 1902, the police began investigating a network of Lithuanian book smugglers and raided Smetona's room where they found a several prohibited Lithuanian publications. He was imprisoned in the Vyborg Castle, but managed to secure acquittal and graduate that spring.

After his graduation from the University in 1902, he moved to Vilnius and worked at the Vilnius Land Bank until 1915. He became an active participant in Lithuanian cultural life and, up until becoming President in December 1926, devoted substantial amounts of time and effort to the Lithuanian press. Two years later, he married Sofija Chodakauskaitė.

From his very first days in Vilnius, Smetona became involved in the activities of various Lithuanian nationalist groups, and joined the Lithuanian Democratic Party, which he represented in the Great Seimas of Vilnius. He was later elected to its Presidium. In 1904 and 1907, he was on the staff of the Lithuanian newspaper, Vilniaus žinios (The Vilnius News). In 1905-1906, he edited the weekly Lietuvos ūkininkas (The Lithuanian Farmer). In 1907, Smetona and the Rev. Juozas Tumas-Vaižgantas established a venture to print the newspaper Viltis (The Hope), and started publishing and circulating it. In Viltis, Smetona advocated national unity. He was also one of the incorporators of the Aušra (Dawn) company for the publishing of Lithuanian books, a member of the Lithuanian Mutual Aid Society of Vilnius, the Lithuanian Learned Society, the Vilniaus aušra (The Dawn of Vilnius), and Rytas (The Morning) education societies, the Rūta Art Society and many other societies, and taught the Lithuanian language at Vilnius schools. In 1914, he started publishing Vairas (The Rudder), a new bi-weekly magazine.

Between 18 and 22 September 1917, he participated in the Lithuanian Conference in Vilnius, and was elected Chairman (1917–1919) of the Council of Lithuania (later Council of the State). On 16 February 1918, Antanas Smetona signed the Act of Independence of Lithuania.

Between December 1918 and March 1919, he lived primarily in Germany and the Scandinavian countries, soliciting loans for the cause of Lithuanian independence. On 4 April 1919, the State Council of Lithuania elected Smetona the first President of the Republic of Lithuania. On 19 April 1920, the Constituent Assembly elected Aleksandras Stulginskis President. Not re-elected to the Seimas, from 1921 to 1924, he edited several periodicals, including Lietuvos balsas (Voice of Lithuania), Lietuviškas balsas (Lithuanian Voice) and Vairas.

In November 1923, authorities imprisoned Smetona for several days for publishing an article by Augustinas Voldemaras in Vairas. Between 1923 and 1927, he was an assistant Professor at the University of Lithuania - at first in the Chair of Art Theory and History and later at the Department of Philosophy. He lectured on ethics, ancient philosophy and Lithuanian linguistics. In 1932, he was awarded an honorary Ph.D. at the Vytautas Magnus University.

Smetona participated in the activity of the Lithuanian Riflemen's Union that had staged the Klaipėda Revolt, which gave him greater name-recognition. More than once, he was elected to its central board. Between 1924 and 1940, he was the vice-Chairman of the Board of the International Bank.

Smetona was one of the Leaders of the coup d'état of 1926, which deposed President Kazys Grinius. He once again became President on 19 December of that year (two others briefly held the office during the coup, which began on 17 December, before Smetona was formally restored to the Presidency). He designated Augustinas Voldemaras as Prime Minister. One year later, he suppressed the parliament and, on 15 May 1928, with the approval of the government, he promulgated a new constitution with more extensive presidential powers. In 1929, he removed Voldemaras and assumed dictatorial powers.

In 1935, Smetona suffered a blow when farmers in south-east Lithuania organised a strike and refused to sell their products. Reprisals led to five deaths and 456 farmers being arrested. This exacerbated long-standing tensions within his regime between hardliners arguing for more rigid totalitarian control over Lithuanian life, and moderates who wanted liberalisation. These difficulties, however, were already becoming overshadowed by the threat of Nazi Germany. Smetona’s regime was the first in Europe to put Nazis on trial: as early as 8 February 1934, action had begun against Nazis in the Memel region, which was autonomous within Lithuania. The Smetona regime’s trial of Ernst Neumann and Freiherr von Sass (July 1934 to March 1935) was the first attempt anywhere to bring Nazis to justice, and saw 76 Hitlerites imprisoned and four sentenced to death – though this was commuted to life imprisonment. By 1938, however, Memel was becoming a difficult issue for a regime spending a quarter of its budget on defence and expensive army modernisation, and the Nazis were able to win 26 of 29 seats in elections. The following year, Smetona surrendered Memel to Hitler and declared a state of emergency – he never lost his distaste for Hitler and Nazism, because he valued the independence of his small nation so firmly.

Lithuania was occupied by Soviet troops in 1940, as a consequence of the 1939 Molotov–Ribbentrop Pact between Nazi Germany and the Soviet Union. After the USSR presented an ultimatum to Lithuania in June of that year, Smetona proposed armed resistance against the Soviets. The majority of the government and the commanders of the army did not concur with the dictator’s proposal, because they believed that effective military resistance was strictly impossible once Soviet troops were stationed inside Lithuania. On 15 June, Smetona turned over the duties of President to Prime Minister Antanas Merkys on an interim basis according to the constitution. Before leaving the Presidential Palace in Kaunas, Smetona said: "I do not want to make Lithuania a bolshevik country with my own hands", and by leaving the country he was hoping to do more for the country's sake by leading a government in exile instead of becoming a Soviet's marionette. He firstly fled to Germany with his family. Shortly afterwards, the Smetonas fled to Switzerland.

Smetona departed Bern for Lisbon in January 1941. Aboard the Serpa Pinto, he reached Rio de Janeiro on 14 February. He was met by local officials and Lithuanian emigrants, and had a meeting with Getúlio Vargas, the President of Brazil. Smetona departed Brazil on 26 February. On 9 or 10 March 1941, Smetona with his wife arrived in New York aboard the SS Argentina. He was greeted by about 30 American journalists and Photographers as well as Lithuanian-American representatives. He was escorted to The Pierre hotel where an evening function with about 400 guests was held on 13 March. Since Smetona was a private individual in the United States, the gathering did not include any members of U.S. organizations.

They lived temporarily at the Embassy of Lithuania in Washington, D.C., but their relationship with the representative Povilas Žadeikis was tense. Smetona then lived in Pittsburgh and Chicago before settling in Cleveland, Ohio in May 1942 with his son's family. While in exile, he began work on a history of Lithuania and on his memoirs. Smetona died in a fire at his son’s house in Cleveland on 9 January 1944, and was buried there. His wife Sofija died in Cleveland on 28 December 1968. The couple were survived by their daughter, Birutė. In 1975, his remains were moved from Cleveland's Knollwood Cemetery mausoleum to All Souls Cemetery in Chardon, Ohio.

In Bern, Smetona met with members of the Lithuanian Diplomatic Service, ambassadors and diplomats who continued to represent pre-occupation Lithuania. They hoped to establish a government-in-exile via the National Committee chaired by former Prime Minister Ernestas Galvanauskas. Smetona saw no need for such a committee and criticized the choice of Galvanauskas. The diplomats were also not receptive to Smetona – he had no funds, authority or political influence. Nevertheless, Smetona signed the so-called Kybartai Act – a backdated document supposedly written in Kybartai before his exile. The Act dismissed Antanas Merkys and appointed Stasys Lozoraitis as both Prime Minister and acting President. This controversial document was never used in practice.

On the morning of 15 June, just after the government decided to accept the Soviet ultimatum, Smetona began making hasty preparations for fleeing the country. He was accompanied by his wife, his son and daughter and their spouses and children, Kazys Musteikis, former Minister of Defense, and two presidential adjutants. Smetona departed Kaunas at about 3 pm that day. They stopped in Kybartai on the border with Nazi Germany. Smetona and Musteikis attempted to summon the 9th Infantry Regiment from Marijampolė to protect them and to offer at least symbolic resistance to the Red Army, but the regiment was stopped by a delegation sent from Kaunas to retrieve the President. Smetona decided to cross the border without delay, but Lithuanian border guards would not allow him to pass. Around midnight, a local man led Smetona, his bodyguard and adjutant across the shallow Liepona stream. With Smetona already on the other side, his family managed to convince border guards to let them through at about 6 am.

Smetona’s government was cautious about industrialisation, as its support base lay in the dominant rural population. As dictator, Smetona did nothing to encourage direct foreign investment, which remained extremely limited throughout his rule. Nonetheless, during Smetona‘s dictatorship, Lithuania did advance economically: industrial output – mainly directed to domestic demand – when he was overthrown by the Soviet invasion was twice what it had been before the coup that brought him to power, and the country’s transport network had been greatly improved by the construction of railways from Šiauliai to Klaipėda and from Kaunas to the south and north-east. In contrast, Smetona was more generous in support for the agricultural sector, which at the time provided almost all of Lithuania’s exports despite occasionally protesting against the regime.