Azikiwe attended various grammar and high schools in Onitsha, Calabar, and Lagos. He spent almost 10 years (1925–34) studying in the United States, where he attended several schools, including Howard University in Washington, D.C. In 1934 he went to the Gold Coast (now Ghana), where he founded a newspaper and was a mentor to Kwame Nkrumah (Nkrumah, Kwame) (first president of Ghana) before returning to Nigeria in 1937. There he founded and edited newspapers and also became directly involved in politics, first with the Nigerian Youth Movement and later (1944) as a founder of the National Council of Nigeria and the Cameroons (NCNC), which became increasingly identified with the Igbo people of southern Nigeria after 1951. In 1948, with the backing of the NCNC, Azikiwe was elected to the Nigerian Legislative Council, and he later served as premier of the Eastern region (1954–59).

Azikiwe led the NCNC into the important 1959 federal elections, which preceded Nigerian independence. He was able to form a temporary government with the powerful Northern Peoples Congress, but its leader, Abubakar Tafawa Balewa (Balewa, Sir Abubakar Tafawa), took the key post of prime minister. Azikiwe received the largely honorary posts of president of the Senate, governor-general, and, finally, president.

In the conflict over Biafra (1967–70), Azikiwe first backed his fellow Igbo, traveling extensively in 1968 to win recognition of Biafra and help from other African countries. In 1969, however, realizing the hopelessness of the war, he threw his support to the federal government. When Olusegun Obasanjo (Obasanjo, Olusegun) turned the government over to civilian elections in 1979, Azikiwe ran unsuccessfully for president as a candidate of a newly formed Nigerian People's Party and retired from politics.

Azikiwe was often at odds with Obafemi Awolowo (Awolowo, Obafemi), a political rival who did not agree with his attempts to form coalition alliances with other ethnic groups, particularly those from the north. An important figure in the history of politics in Nigeria, Azikiwe had broad interests outside that realm. He served as chancellor of the University of Nigeria at Nsukka from 1961 to 1966, and he was the president of several sports organizations for football, boxing, and table tennis. Among his writings is an autobiography, My Odyssey: An Autobiography (1970).