Leopold was born in Brussels on 9 April 1835. He was the second child of the reigning Belgian monarch, Leopold I, and his second wife, Louise, the daughter of King Louis Philippe of France. The French Revolution of 1848, which spared Belgium, forced Louis Philippe to flee to the United Kingdom, of which Leopold's first cousin Queen Victoria was monarch. The royal families of Belgium and the United Kingdom were linked by numerous marriages, and were additionally both descended from the House of Saxe-Coburg and Gotha. Louis Philippe died two years later, in 1850. Leopold's fragile mother was deeply affected by the death of her father, and her health deteriorated. She died that same year, when Leopold was 15 years old.

9 April 1853: Leopold was given the Grand Cordon of the Order of Leopold by his father, as a gift for his 18th birthday.

Leopold's reign was marked by a number of major political developments. The Liberals governed Belgium from 1857 to 1880, and during its final year in power legislated the Frère-Orban Law of 1879. This law created free, secular, compulsory primary schools supported by the state and withdrew all state support from Roman Catholic primary schools. The Catholic Party obtained a parliamentary majority in 1880, and four years later restored state support to Catholic schools. In 1885, various socialist and social democratic groups drew together and formed the Labour Party. Increasing social unrest and the rise of the Labour Party forced the adoption of universal male suffrage in 1893.

Leopold became king in 1865. He explained his goal for his reign in an 1888 letter addressed to his brother, Prince Philippe, Count of Flanders: "the country must be strong, prosperous, therefore have colonies of her own, beautiful and calm."

In 1866, Leopold instructed the Belgian ambassador in Madrid to speak to Queen Isabella II of Spain about ceding the Philippines to Belgium. Knowing the situation fully, the ambassador did nothing. Leopold quickly replaced the ambassador with a more sympathetic individual to carry out his plan. In 1868, when Isabella II was deposed as queen of Spain, Leopold tried to press his original plan to acquire the Philippines. But without funds, he was unsuccessful. Leopold then devised another unsuccessful plan to establish the Philippines as an independent state, which could then be ruled by a Belgian. When both of these plans failed, Leopold shifted his aspirations of colonisation to Africa.

Four children were born of this marriage, three daughters and one son, also named Leopold. The younger Leopold died in 1869 at the age of nine from pneumonia after falling into a pond. His death was a source of great sorrow for King Leopold, who had lost his only heir. The marriage became unhappy, and the couple separated completely after a last attempt to have another son, a union that resulted in the birth of their last daughter Clementine. Marie Henriette retreated to Spa in 1895, and died there in 1902.

Leopold was the founder and sole owner of the Congo Free State and all its people, a private project undertaken on his own behalf. He used Explorer Henry Morton Stanley to help him lay claim to the Congo, an area now known as the Democratic Republic of the Congo. At the Berlin Conference of 1884–1885, the colonial nations of Europe authorised his claim by committing the Congo Free State to improving the lives of the native inhabitants. From the beginning, Leopold ignored these conditions and millions of Congolese inhabitants, including children, were mutilated and killed. He ran the Congo using the mercenary Force Publique for his personal enrichment. He used great sums of the money from this exploitation for public and private construction projects in Belgium during this period. He donated the private buildings to the state before his death.

After numerous unsuccessful schemes to acquire colonies in Africa and Asia, in 1876 Leopold organized a private holding company disguised as an international scientific and philanthropic association, which he called the International African Society, or the International Association for the Exploration and Civilization of the Congo. In 1878, under the auspices of the holding company, he hired Explorer Henry Stanley to explore and establish a colony in the Congo region. Much diplomatic maneuvering among European nations resulted in the Berlin Conference of 1884–1885 regarding African affairs, at which representatives of 14 European countries and the United States recognized Leopold as sovereign of most of the area to which he and Stanley had laid claim. On 5 February 1885, the Congo Free State, an area 76 times larger than Belgium, was established under Leopold II's personal rule and private army, the Force Publique.

Leopold amassed a huge personal fortune by exploiting the natural resources of the Congo. At first, ivory was exported, but this did not yield the expected levels of revenue. When the global demand for rubber exploded, attention shifted to the labor-intensive collection of sap from rubber plants. Abandoning the promises of the Berlin Conference in the late 1890s, the Free State government restricted foreign access and extorted forced labor from the natives. Abuses, especially in the rubber industry, included forced labor of the native population, beatings, widespread killings, and frequent mutilation when production quotas were not met. Missionary John Harris of Baringa was so shocked by what he had encountered that he wrote to Leopold's chief agent in the Congo, saying:

The first revision of the Belgian constitution came in 1893. Universal male suffrage was introduced, though the effect of this was tempered by plural voting. The eligibility requirements for the senate were reduced, and elections would be based on a system of proportional representation, which continues to this day. Leopold pushed strongly to pass a royal referendum, whereby the king would have the power to consult the electorate directly on an issue, and use his veto according to the results of the referendum. The proposal was rejected, as it would have given the king the power to override the elected government. Leopold was so disappointed that he considered abdication.

In 1894, King Leopold signed a treaty with Great Britain which conceded a strip of land on the Congo Free State's eastern border in exchange for the Lado Enclave, which provided access to the navigable Nile and extended the Free State's sphere of influence northwards into Sudan. After rubber profits soared in 1895, Leopold ordered the organization of an expedition into the Lado Enclave, which had been overrun by Mahdist rebels since the outbreak of the Mahdist War in 1881. The expedition was composed of two columns: the first, under Belgian war hero Baron Dhanis, consisted of a sizable force, numbering around 3,000, and was to strike north through the jungle and attack the rebels at their base at Rejaf. The second, a much smaller force of 800, was led by Louis-Napoléon Chaltin and took the main road towards Rejaf. Both expeditions set out in December 1896.

Leopold commissioned a great number of buildings, urban projects and public works, largely with the profits generated from exploitation of natural resources from the Congo. These projects earned him the epithet of "Builder King" (Koning-Bouwheer in Dutch, le Roi-Bâtisseur in French). The public buildings were mainly in Brussels, Ostend and Antwerp, and include the Hippodrome Wellington racetrack, the Royal Galleries and Maria Hendrikapark in Ostend; the Royal Museum for Central Africa and its surrounding park in Tervuren; the Cinquantenaire park, triumphal arch and complex, and the Duden Park in Brussels, and the 1895-1905 Antwerpen-Centraal railway station.

Smallpox epidemics and sleeping sickness also devastated the disrupted population. By 1896, African trypanosomiasis had killed up to 5,000 Africans in the village of Lukolela on the Congo River. The mortality statistics were collected through the efforts of British consul Roger Casement, who found, for Example, only 600 survivors of the disease in Lukolela in 1903.

Although Leopold had initially planned for the expedition to carry on much farther than the Lado Enclave, hoping indeed to take Fashoda and then Khartoum, Dhanis' column mutinied in February 1897, resulting in the death of several Belgian officers and the loss of his entire force. Nonetheless, Chaltin continued his advance, and on 17 February 1897, his outnumbered forces defeated the rebels in the Battle of Rejaf, securing the Lado Enclave as a Belgian territory until Leopold's death in 1909.

Leopold had many mistresses. In 1899, in his sixty-fifth year, Leopold took as a mistress Caroline Lacroix, a sixteen-year-old French prostitute, and they remained together for the next decade until his death. Leopold lavished upon her large sums of money, estates, gifts, and a noble title, Baroness Vaughan. Owing to these gifts and the unofficial nature of their relationship, Caroline was deeply unpopular among the Belgian people and internationally. She and Leopold married secretly in a religious ceremony five days before his death. Their failure to perform a civil ceremony rendered the marriage invalid under Belgian law. After the king's death, it was soon discovered that he had left Caroline a large fortune, which the Belgian government and Leopold's three estranged daughters tried to seize as rightfully theirs. Caroline bore two sons who were probably Leopold's; the boys would have had a strong claim to the throne had the marriage been valid.

Thinking of the Future after his death, Leopold did not want the collection of estates, lands and heritage buildings he had privately amassed to be scattered amongst his daughters, each of whom was married to a foreign Prince. In 1900, he created the Royal Trust, by means of which he donated most of his property to the Belgian nation. This preserved them to beautify Belgium in perpetuity, while still allowing Future generations of the Belgian Royal family the privilege of their use.

On 15 November 1902, Italian anarchist Gennaro Rubino attempted to assassinate Leopold, who was riding in a royal cortege from a ceremony at Saint-Gudule Cathedrale in memory of his recently deceased wife, Marie Henriette. After Leopold's carriage passed, Rubino fired three shots at the procession. The shots missed Leopold but almost killed the king's Grand Marshall, Count Charles John d'Oultremont. Rubino was immediately arrested and subsequently sentenced to life imprisonment. He died in prison in 1918.

International opposition and criticism from both the Catholic Party and the Labour Party caused the Belgian parliament to compel the king to cede the Congo Free State to Belgium in 1908. The deal that led to the handover cost Belgium the considerable sum of 215.5 million Francs. This was used to discharge the debt of the Congo Free state and to pay out its bond holders as well as 45.5 million for Leopold's pet building projects in Belgium and a personal payment of 50 million to him. The Congo Free State was transformed into a Belgian colony known as the Belgian Congo under parliamentary control. Leopold went to great lengths to conceal potential evidence of wrongdoing during his time as ruler of his private colony. The entire archive of the Congo Free State was burned and he told his aide that even though the Congo had been taken from him, "they have no right to know what I did there". After gaining its independence in the mid-20th century, it was renamed three times: first, as the Republic of the Congo; second as Zaire, the name it retained under Mobutu Sese Seko's dictatorship; and third as the Democratic Republic of the Congo, or DRC. (This is not to be confused with the neighboring Republic of the Congo, which was formerly a colony of France.)

On 17 December 1909, Leopold II died at Laeken, and the Belgian crown passed to Albert, the son of Leopold's brother, Philip, Count of Flanders. His funeral cortege was booed by the crowd. Leopold's reign of exactly 44 years remains the longest in Belgian history. He was interred in the royal vault at the Church of Our Lady of Laeken in Brussels.

Leopold also fathered two sons by Caroline Lacroix. They were adopted in 1910 by Lacroix's second husband, Antoine Durrieux. Leopold granted them courtesy titles that were honorary, as the parliament would not have supported any official act or decree:

Adam Hochschild devotes a chapter of his book King Leopold's Ghost to the Problem of estimating the death toll. He cites several recent lines of investigation, by Anthropologist Jan Vansina and others, that examine local sources (police records, religious records, oral traditions, genealogies, personal diaries, and "many others"), which generally agree with the assessment of the 1919 Belgian government commission: roughly half the population perished during the Free State period. Hochshild points out that since the first official census by the Belgian authorities in 1924 put the population at about 10 million, these various approaches suggest a rough estimate of a total of 10 million dead.

Estimates of the death toll range from one million to fifteen million, since accurate records were not kept. Historians Louis and Stengers in 1968 stated that population figures at the start of Leopold's control are only "wild guesses", and that attempts by E. D. Morel and others to determine a figure for the loss of population were "but figments of the imagination".

After the king's death and transfer of his private colony to Belgium, there occurred a "Great Forgetting". Many Belgians in the 20th and 21st centuries remember Leopold II as the "Builder King" for his extensive public works projects, and many remain unaware of his role in the atrocities in the Congo. In the 1990s, the colonial Royal Museum for Central Africa made no mention of the atrocities committed in the Congo Free State, despite the museum's large collection of colonial objects. On the boardwalk of Blankenberge, a popular coastal resort, a monument shows a pair of colonists as heroes protecting a desperate Congolese woman and child with "civilization". In Ostend, the beach promenade has a 1931 sculptural monument to Leopold II, showing Leopold and grateful Ostend fishermen and Congolese. The inscription accompanying the Congolese group notes: "De dank der Congolezen aan Leopold II om hen te hebben bevrijd van de slavernij onder de Arabieren" ("The gratitude of the Congolese to Leopold II for having liberated them from slavery under the Arabs"). In 2004, an Activist group cut off the hand of the leftmost Congolese bronze figure, in protest against the atrocities committed in the Congo. The city council decided to keep the statue in its new form, without the hand.

Leopold II remains a controversial figure in the Democratic Republic of Congo. His statue in the capital Kinshasa was removed after independence. Congolese culture minister Christophe Muzungu decided to reinstate the statue in 2005. He noted that the beginning of the Free State had been a time of some economic and social progress. He argued that people should recognize some positive aspects of the king as well as the negative; but hours after the six-metre (20 ft) statue was installed near Kinshasa's central station, it was officially removed.

He had four children with Queen Marie-Henriette, of whom the youngest two have descendants living as of 2018:

Inspired by works such as Joseph Conrad’s Heart of Darkness (1902), originally published as a three-part series in Blackwood’s Magazine (1899) and based on Conrad's experience as a steamer captain on the Congo 12 years earlier, international criticism of Leopold’s rule increased and mobilized. Reports of outrageous exploitation and widespread human rights abuses led the British Crown to appoint their consul Roger Casement to investigate conditions there. His extensive travels and interviews in the region resulted in the Casement Report, which detailed the extensive abuses under Leopold's regime. A widespread war of words ensued. In Britain, former shipping clerk E. D. Morel with Casement's support founded the Congo Reform Association, the first mass human rights movement. Supporters included American Writer Mark Twain, whose stinging political satire entitled King Leopold's Soliloquy portrays the king arguing that bringing Christianity to the country outweighs a little starvation, and uses many of Leopold's own words against him.