While studying in the United States, Nkrumah was influenced by the socialist writings of German political philosopher Karl Marx, German political economist Friedrich Engels, and Russian revolutionary leader Vladimir Lenin. Nkrumah formed an African students organization and became a popular speaker, advocating the liberation of Africa from European colonialism. He also promoted Pan-Africanism, a movement for cooperation between all people of African descent and for the political union of an independent Africa. In 1945 he went to London, England, to study economics and law. That year he helped organize the fifth Pan-African Congress, in Manchester, England. This congress brought together black leaders and intellectuals from around the world to declare and coordinate opposition to colonialism in Africa. At the congress, Nkrumah met many important African and African American leaders, including black American sociologist and writer W. E. B. Du Bois, future president of Kenya Jomo Kenyatta, and American actor and civil rights activist Paul Robeson. In 1946 Nkrumah left his academic studies to become secretary general of the West African National Secretariat, which had been formed at the fifth Pan-African Congress to coordinate efforts to bring about West African independence. That same year, Nkrumah became vice president of the West African Students Union, a pro-independence organization of younger, more politically aggressive African students studying in Britain.

Nkrumah returned to the Gold Coast in 1947 when the United Gold Coast Convention (UGCC), a nationalist party, invited him to serve as its secretary general. In this capacity he gave speeches all over the colony to rally support for the UGCC and for independence. In 1948 a UGCC-organized boycott of foreign products led to riots in Accra, and Nkrumah and several other UGCC leaders were arrested by British colonial authorities and briefly imprisoned. In 1948 Nkrumah split with the UGCC leadership, which he viewed as too conservative in its efforts to win independence, and formed his own political party, the Convention People's Party (CPP). After organizing a series of colony-wide strikes in favor of independence that nearly brought the colony's economy to a standstill, Nkrumah was again imprisoned for subversion in 1950. However, the strikes had convinced the British authorities to establish a more democratic colonial government and move the colony toward independence. In 1951 elections for the colonial legislative council, the CPP won most of the seats and Nkrumah, while still in prison, won the central Accra seat by a landslide. The British governor of the Gold Coast released Nkrumah from prison and appointed him leader of government business. The following year he named Nkrumah prime minister. Reelected in 1954 and 1956, Nkrumah guided the Gold Coast to independence in 1957 under the name Ghana, after an ancient West African empire.

Nkrumah built a strong central government and attempted to unify the country politically and to muster all its resources for rapid economic development. As a proponent of Pan-Africanism, he sought the liberation of the entire continent from colonial rule, offered generous assistance to other African nationalists, and initially pursued a policy of nonalignment with either the United States or the Union of Soviet Socialist Republics (USSR). When most other African colonies became independent in the early 1960s, Nkrumah urged them to unite with Ghana to form a United States of Africa. His goal was never realized, but his efforts helped bring about the Organization of African Unity, which promotes peace and cooperation between African nations. In 1960 Ghana became a republic and Nkrumah was elected president.

Between 1961 and 1966 Nkrumah spearheaded an ambitious and very expensive hydroelectric project on the Volta River that was highly successful. He was accused of economic mismanagement in the Volta River project and several other expensive developmental schemes over this same period. Nkrumah did not hesitate to use strong-arm methods in implementing his domestic programs. These measures included passing laws allowing the imprisonment of political opponents without charge, and dismissing the nation's supreme court and pronouncing judgments himself. Although he remained popular with the masses, his tactics made enemies among civil servants, judges, intellectuals, and army officers. Nkrumah also fell out of favor with Western powers in the mid-1960s by courting development aid from the USSR and other Communist states. He was accused of fostering a personality cult, as his supporters called him Osagyefo ("the redeemer" or "warrior"), and became increasingly influenced by government ministers and businesspeople who used flattery to obtain favorable decisions from him. Assassination attempts in 1962 and 1964 made him grow more and more paranoid; he had numerous critics of his regime arrested, and in 1964 he declared the CPP the only legal party. While Nkrumah was visiting China in 1966, his government was overthrown in an army coup. Nkrumah lived in exile in Guinea, where Guinean president S©kou Tour© appointed him honorary co-president of Guinea. He died in 1972 in Romania while receiving treatment for throat cancer. Nkrumah's remains were returned to Ghana for burial in his home town of Nkroful.