Modibo Keïta was involved in various associations. In 1937, he was the coordinator of the art and theater group. Along with Ouezzin Coulibaly, he helped found the Union of French West African Teachers. Keïta joined the Communist Study Groups (GEC) cell in Bamako.

In 1943, he founded the L'oeil de Kénédougou, a magazine critical of colonial rule. This led to his imprisonment for three weeks in 1946 at the Prison de la Santé in Paris. In 1945 Keïta was a candidate for the Constituent Assembly of the French Fourth Republic, supported by GEC and the Sudanese Democratic Party. Later the same year, he and Mamadou Konaté founded the Bloc soudanais, which developed into the Sudanese Union.

In October 1946, the African Democratic Rally (RDA) was created at a conference in Bamako of delegates from across French Africa. While the coalition was led by Félix Houphouët - Boigny, Keïta assumed the post of RDA Secretary - General in French Sudan, and head of the Soundanese affiliate: the US-RDA. In 1948, he was elected general councilor of French Sudan. In 1956, he was elected mayor of Bamako and became a member of the National Assembly of France. He twice served as secretary of state in the governments of Maurice Bourgès - Maunoury and Félix Gaillard. Modibo Keïta was elected constituent assembly president of the Mali Federation on July 20, 1960, which consisted of French Sudan, and Senegal. Senegal would later leave the federation.

After the collapse of the federation, the US-RDA proclaimed the Soudanese Republic's complete independence as the Republic of Mali. Keita became its first president.

As a socialist, he led his country towards the progressive socialization of the economy; at first starting with agriculture and trade, then on October 1960 creating the SOMIEX (Malian Import and Export Company), which had a monopoly over the exports of the products of Mali, as well as manufactured and food imports (e.g. sugar, tea, powdered milk) and their distribution inside the country. The establishment of the Malian franc in 1962, and the difficulties of provisioning, resulted in a severe inflation and dissatisfaction of the population, particularly the peasants and the businessmen.

Although Keita was initially viewed by the United States as a socialist, he made it clear that he sought good relations with Washington. In September 1961, he travelled to America in the company of Sukarno and met with President John F. Kennedy. Keita, afterward, felt that he had a friend in Kennedy.

On the political level, Modibo Keïta quickly imprisoned opponents like Fily Dabo Sissoko. From 1967, he started the "revolution active" and suspended the constitution by creating the National Committee for the Defense of the Revolution (CNDR). The exactions of the "milice populaire" (the US-RDA militia) and the devaluation of the Malian franc in 1967 brought a general unrest.

On November 19, 1968, the General Moussa Traoré organized a coup d'etat against Modibo Keïta, and sent him to prison in the northern Malian town of Kidal.

After being transferred back to the capital Bamako in February 1977 in what was claimed to be an action by the government towards national reconciliation in preparation for his release; but Modibo Keïta died, still a prisoner, on May 16, 1977. His reputation was rehabilitated in 1992 following the overthrow of Moussa Traoré and subsequent elections of president Alpha Oumar Konaré. A monument for Modibo Keita, was dedicated in Bamako on June 6, 1999.

Modibo Keïta devoted his entire life to African unity. He first played a part in the creation of the Federation of Mali with Léopold Sédar Senghor. After its collapse, he moved away from Léopold Sédar Senghor, but with Sékou Touré, the president of Guinea, and Kwame Nkrumah, the President of Ghana, he formed the Union of the States of Western Africa. In 1963, he played an important role in drafting the charter of the Organization of African Unity (OAU).

In 1963, he invited the king of Morocco and the president of Algeria to Bamako, in the hope of ending the Sand War, a frontier conflict between the two nations. Along with Emperor Haile Selassie of Ethiopia, Keita was successful in negotiating the Bamako Accords, which brought an end to the conflict. As a result, he won the Lenin Peace Prize that year.

From 1963 to 1966, he normalized relations with the countries of Senegal, Upper Volta and Côte d'Ivoire. An advocate of the Non-Aligned Movement, Modibo defended the nationalist movements like the Algerian National Liberation Front (FLN).