Azikiwe was born on 16 November 1904, in Zungeru, Northern Nigeria. Nnamdi means "My father is alive" in the Igbo language. His parents were Igbo; his father Obed-Edom Chukwuemeka Azikiwe (1879–1958), an Onitsha-indigene and clerk in the British Administration of Nigeria who traveled extensively because of the nature of his job. Zik's mother was Rachel Chinwe Azikiwe sometimes called Nwanonaku whose family was descended from a royal house in Onitsha; her paternal great grandfather was Obi Anazenwu. Azikiwe had one sibling, a sister named Cecilia Eziamaka Arinze. Growing up as a young boy in Northern Nigeria, Azikiwe spoke Hausa, the language of the region, however, his father apprehensive of his child's fluency in Hausa and not Igbo sent him to Onitsha in 1912 to live with his paternal grandmother and aunt in order to learn the Igbo language and culture. In Onitsha, he attended Holy Trinity School, a Roman Catholic Mission school and then Christ Church School, an Anglican primary school. In 1914, his father was working in Lagos and when Azikiwe was bitten by a dog, his father worried about Zik's health asked him to come to Lagos so as to heal and also attend school in the city. Two years later, his father was posted out of Lagos to Kaduna and Azikiwe briefly lived with a relative who was married to a Muslim from Sierra Leone. He was back in Onitsha by 1918 and finished his elementary education at CMS Central School where he also served as a pupil-teacher supporting his mother with some of his earnings. In 1920, his father was posted back to Southern Nigeria in the Southeastern city of Calabar. Zik joined his father in Calabar and started his secondary school at Hope Waddell Training College. In Calabar, he was introduced to the teachings of Marcus Garvey, Garveyism later an important part in his nationalistic rhetoric.

He made a name for himself in the professional world. The many posts he held included: Third-class Clerk, Treasury Department, Lagos (1921–24); Recruit, Gold Coast Police Force (July–September 1924); Solicitor Clerk to the late Mr. Justice Graham Paul at Calabar (January – August 1925); Instructor in Political Science, Lincoln University (1931–34); University Correspondent for the Baltimore Afro-American (1928–34); General and Sports Correspondent for the Philadelphia Tribune (1928–34); Editor-in Chief of the West African Pilot (1937–45); Correspondent for the Associated Negro Press (1944–47); Correspondent for Reuters (1944–46); Managing Director of Zik's Press Limited printers and publishers of the West African Pilot (Lagos), Eastern Guardian (Port Harcourt), Nigerian Spokesman (Onitsha), Southern Nigeria Defender (Ibadan), Daily Comet (Kano), and Eastern Sentinel (Enugu); Managing Director of Comet Press Limited (1945–53); Chairman of West African Pilot Limited and the Associated Newspapers of Nigeria Limited and six other limited liability companies (1952–53); Chairman, Nigerian Real Estate Corporation Limited (1952–53).

Azikiwe was actively involved in Sports at every stage of his life, and he was successful in many of the events that he participated in. They include Welterweight Boxing Champion Storer College (1925–27); High Jump champion, Howard University Inter-Scholastic Games (1926); Gold Medalist in Cross Country, Storer College (1927); Back-stroke Swimming Champion and No. 3 Swimmer in Freestyle Relay team, Howard University (1928); Captain, Lincoln University Soccer Team (1930); Winner Two Miles Run, Central Inter-Collegiate Athletic Association Championships at Hampton Institute Virginia (1931); Bronze Medalist, Richmond Cross Country Marathon (1931); Gold Medalist in the 1,000 yard run, One Mile Run and Three Mile Run, Catedonian Games in Brooklyn, NY (1932); Silver Trophy winner in the Half Mile race, and Silver Cup winner in the One Mile Race, Democratic Field Day Championships, New Haven, Connecticut (1933); Runner-up (with G. K. Dorgu) at the Lagos Tennis Men's Double Championships (Division B 1938); anchor man for the ZAC team which won the 50 yards Freestyle Relay at the Lagos Swimming Championships (1939).

Azikiwe first attended Storer College, a two-year preparatory school, in Harpers Ferry, West Virginia. In U.S he took to doing various odd jobs to support his tuition and living expenses. He initially struggled working without a major sponsorship and also feeling lonesome and depressed, feelings he later overcame. Azikiwe participated in Storer's athletics and cross-country teams before he transferred to Howard University, Washington DC, He then enrolled and graduated from Lincoln University, Pennsylvania, in 1930, obtaining a master's degree in Religion from Lincoln University in 1932 and another master's degree in Anthropology from University of Pennsylvania in 1934. Azikiwe became a graduate student instructor in the history and political science department at Lincoln creating an African history course. He was a candidate for a doctorate degree from Columbia before returning to Nigeria in 1934. His main doctorate research was Liberia in world politics and the research paper was published by A.H. Stockwell in 1934. During the time he was in America, Azikiwe was a columnist for the Baltimore Afro-American, Philadelphia Tribune and the Associated Negro Press. He was influenced by the ideals of the African American press, Garveyism and Pan-Africanism while writing for those papers.

Azikiwe applied to become a foreign Service official for Liberia but was rejected because he was not a native of Liberia. By 1934, when he returned to Lagos, he was already well known and a viewed as a public figure among some members of the Lagos and Igbo community. On his return, he was welcomed by a multitude of people, a sign that his writings in America had reached Nigeria. In Nigeria, his initial goal was to seek an appropriate appointment in Nigeria that was commensurate with his education but after several applications including a teaching job at King's College and getting no positive response, he took an offer from Ghanaian businessman Alfred Ocansey to become the founding Editor African Morning Post, a daily newspaper in Accra, Ghana. Zik was given a free hand to run the newspaper and recruited many of the pioneer staff. Azikiwe wrote a column for the paper tagged Inside Stuff by Zik, a platform which he used for radical nationalistic and black pride preachment but generated alarm within colonial circles. As Editor, he promoted a pro-African nationalist agenda. Smertin has described his writing there: "In his passionately denunciatory articles and public statements he censured the existing colonial order: the restrictions on the Africans' right to express their opinions, and racial discrimination. He also criticised those Africans who belonged to the "elite" of colonial society and favoured retaining the existing order, as they regarded it as the basis of their well being." It was during his period in Accra that he advanced his idea of New Africa, a black pride philosophy that was expanded in his published book, Renascent Africa. The New Africa is a state where Africans will be divorced from ethnic affiliations and traditional authorities and transformed by five philosophical pillars of spiritual balance, social regeneration, economic determinism, mental emancipation and national Risorgimento. In the Gold coast, Azikiwe did not shy away from local politics and the paper supported the local Mambii party.

During his lifetime, he held several political posts, especially in Nigeria. They include Executive Committee Member of Mambili Party, Accra (1935–37); General Secretary of National Council of Nigerian and the Cameroons (1944–45); President of the NCNC (1946–60); Vice-President of the Nigerian National Democratic Party (1947–60); Member for Lagos in the Legislative Council of Nigeria (1947–51); Member for Lagos and Leader of the Opposition in the Western House of Assembly (1952–53) Member for Onitsha in the Eastern House of Assembly (1954–60); Minister of Internal Affairs (Jan.–September 1954); Minister of Internal Affairs, Eastern Region (1954); Member of His Excellency Privy Council, Eastern Nigeria (1954–59); Primer of Eastern Nigeria (1954–59); President of the Senate of the Federation (January–November 1960); Governor-General and Commander-in-Chief of Nigeria (1960–63); President of the Republic of Nigeria (1963–1966); and Chairman and Presidential candidate of the Nigeria People's Party (1978–83).

As a result of publishing an article on 15 May 1936, entitled "Has the African a God?" written by I. T. A. Wallace-Johnson, he was brought to trial on charges of sedition. Although he was found guilty of the charges and sentenced to six months in prison, he was acquitted on appeal. He returned to Lagos, Nigeria in 1937 and started the West African Pilot, a newspaper he used to promote Nigerian nationalism. Along with the Pilot, he started a string of newspapers under the Zik Group of Newspapers in politically and economically important cities across the country. The flagship newspaper of the group was West African Pilot which used Dante Alighieri's "Show the light and the people will find the way as motto." The others papers in the group included The Southern Nigeria Defender from Warri and later Ibadan, Eastern Guardian founded in 1940 and published in Port Harcourt, and Nigerian Spokesman at Onitsha. In 1944, the group acquired Duse Mohamed's the Comet. Zik's newspaper venture was both a Business and a political tool. To succeed as a Business, the Pilot gave less attention to advertising and focused more on its circulation largely because expatriate firms dominated the Nigerian economy. Many of Zik's newspapers placed emphasis on sensationalism and human interest stories; the Pilot introduced a women's section and introduced coverage of Sports and increasing its Nigerian content against main competitor, the Daily Times expatriate and foreign news Service dominated stories. The pilot started with an initial run of 6,000 copies daily and at its peak in 1950, it was printing over 20,000 copies. During the paper's run, Zik established a few other Business ventures such as African Continental Bank and Penny restaurant and used his newspapers as a medium to advertise these ventures.

Prior to World War II, the West African Pilot was not overtly radical but trying to build up a readership base, the paper's politics focused on injustice to Africans, criticism of colonial administration and supported many of the ideas of the educated elites in Lagos. However, by 1940, a gradual change occurred, like the African Morning Post, Zik started a column, Inside Stuff which was sometimes used to arouse political consciousness and in the Pilot's editorials, opinions were written for independence in Africa especially after the rise of the Indian independence movement. Though, it supported Great Britain in World War II, the Pilot was critical of war policies such as price controls and wage ceilings. In 1943, when the British Council sponsored 8 West African editors including Azikiwe. Azikiwe and six other editors used the opportunity to raise awareness about political independence. The journalists signed a memorandum calling for gradual socio-political reforms that will include abrogation of the crown colony system, installing representative system in regions and granting independence to British West African colonies by 1958 or 1960 . However, the memorandum was ignored by the colonial office and the indifference furthered Zik's militancy.

Azikiwe became active in the Nigerian Youth Movement (NYM), the first genuinely nationalist organization in Nigeria. However, in 1941 he backed Samuel Akinsanya to be NYM candidate for a vacant seat in the Legislative Council, but the executive selected Ernest Ikoli instead. Azikiwe resigned from the NYM accusing the majority Yoruba leadership of discrimination against the Ijebu-Yoruba members, Ibos and some Ijebu members with him, thus splitting the NYM along ethnic lines.

After a successful journalism enterprise, Azikiwe entered active politics, co-founding the National Council of Nigeria and the Cameroons (NCNC) alongside Herbert Macaulay in 1944. He became the secretary-general of the National Council in 1946.

In 1945, British governor, Arthur Richards presented proposals for a revision of the Clifford constitution of 1922, included in the proposal was an increase in the number of nominated African members to the Legislative Council. However, the new changes met opposition from nationalists such as Azikiwe. NCNC politicians opposed the unilateral decisions made by Richards and constitutional provision that allowed for only four elected African members while the rest were to be nominated candidates. The nominated African candidates were described as mostly loyal to the colonial government and would not aggressively seek self-government. Another basis of opposition was there was little input for the advancement of Africans into senior positions in the civil Service. NCNC opposed Richards proposals and made preparations to argue its case to the new labour government in Britain. A tour of the country was embarked on to raise awareness about the party's concerns and to also raise money for the U.K. protest. During of one the tour, NCNC's President, Herbert Macaulay died and Azikiwe carried on with leadership of the party. Azikiwe now the leader of NCNC also led the delegation to London, in preparation for the trip, he traveled to U.S. to gain sympathy for the party's case and met a few individuals such as Mrs. Roosevelt at Hyde Park and making a speech about the"emancipation of Nigeria from the political thralldom, economic insecurity and social disabilities". The U.K. delegation which included Azikiwe as others Leaders had Funmilayo Ransome-Kuti, Zanna Dipcharima, Abubakar Olorunimbe, Adeleke Adedoyin and Nyong Essien visited the Fabian Colonial Bureau, the Labor Imperial Committee and the West African Students' Union to raise awareness about its proposals for amendments to the 1922 constitution. Included in NCNC's proposals was consultation with Africans about changes in Nigerian constitution, more power provided to the regional House of Assemblies and limiting the powers of the central Legislative Council to matters affecting defense, currency and foreign affairs. The delegation submitted its proposals to the colonial secretary but little was done to make changes to Richard's proposals. The Richards Constitution was allowed to take effect on 1947 and Azikiwe contested for one of the Lagos seats to stall the implementation of the new constitution.

He was inducted into the prestigious Agbalanze society of Onitsha as Nnanyelugo in 1946, a customary recognition for Onitsha men of significant accomplishment. Then, in 1962, he became a second-rank red cap chieftain or Ndichie Okwa as the Oziziani Obi. In 1972, he was installed as the Owelle-Osowa-Anya of Onitsha, making him a first-rank, hereditary red cap nobleman or Ndichie Ume.

Under the Richards constitution, Azikiwe was elected to Legislative Council of Nigeria in a Lagos municipal election under the banner of the National Democratic Party, a subsidiary of NCNC. However, he and the party's representative did not attend the first session of the council and agitation for changes to the Richard's Constitution led to the Macpherson Constitution. A modified constitution, the Macpherson Constitution took effect in 1951 and called for Nigerian elections to the regional House of Assembly, like the Richards Constitution, Azikiwe opposed the new changes but he chose to contest with the Desire of being selected as a House of Representatives member which will give him a chance to make changes to the constitution. Staggered elections were held Nigeria from August to December, 1951. In the Western region were Azikiwe contested, two parties were dominant, Azikiwe's NCNC and the Acton Group. The regional elections to the Western Regional Assembly was held in September and December 1951 because the constitution only allowed for an electoral college to choose members of the national legislature, the chance of an Action Group majority in the house could prevent Azikiwe from going to the House of Representatives. Azikiwe won a regional assembly seat from Lagos but the opposition party claimed majority victory in the House of Assembly and Azikiwe was denied the opportunity to represent Lagos in the Federal House of Representatives. In 1951, he became the leader of the Opposition to the government of Obafemi Awolowo in the Western Region's House of Assembly. The choice of not selecting Azikiwe to the national assembly precipitated a series of chaos in the West An internal agreement by elected NCNC members from Lagos to step down for Azikiwe in the inevitability that Azikiwe will not be nominated broke down. Azikiwe blamed the constitution and wanted changes to be made. The NCNC which dominated the Eastern region also followed Azikiwe's views and was committed to see the constitution be amended.

In 1952, he moved to the Eastern Region, and the NCNC dominated regional assembly made proposals to accommodate him. The regional and central ministers of the party were asked to resign for a cabinet reshuffle but majority of the ministers ignored the resignation call The regional assembly then passed a vote of no confidence on the ministers and any appropriation bill sent to the ministry was rejected. This created an impasse in the region and the Lt. Gov dissolved the regional house. A new election returned Azikiwe as a member of the Eastern Assembly. He was selected to the position of Chief Minister and in 1954 became Premier of Nigeria's Eastern Region when it was made a Federating unit.

In 1960, He established the University of Nigeria, Nsukka and Queen Elizabeth II appointed him to the Privy Council of the United Kingdom. He was conferred with the highest national honour of Grand Commander of the Federal Republic (GCFR) by the Federal Republic of Nigeria, in 1980.

Azikiwe and his civilian colleagues were removed from power in the military coup of 15 January 1966. He was the most prominent Politician to escape the spate of assassinations following the coup. During the Biafran (1967–1970) war of secession, Azikiwe became a spokesman for the nascent republic and an adviser to its leader Chukwuemeka Odumegwu Ojukwu. He switched allegiance back to Nigeria during the war and publicly appealed to Ojukwu to end the war in pamphlets and interviews published at the time. Writing on his politics, the New York Times note that, "Throughout his life, Dr. Azikiwe's alliance with northerners put him at odds with Obafemi Awolowo, a socialist-inclined leader of the Yoruba, the country's other important southern group.″ After the war, he served as Chancellor of University of Lagos from 1972 to 1976. He joined the Nigerian People's Party in 1978, making unsuccessful bids for the presidency in 1979 and again in 1983. He left politics involuntarily after the military coup on 31 December 1983. He died on 11 May 1996, at the University of Nigeria Teaching Hospital, in Enugu, Enugu State, after a protracted illness. He was buried in his native Onitsha.

Upon his death The New York Times comments that Nnamdi “towered over the affairs of Africa’s most populous nation, attaining the rare status of a truly national hero who came to be admired across the regional and ethnic lines dividing his country.” Quite the honor from one of the best publications of modern times.