Upon graduating in 1956, he held a succession of jobs in various locations throughout the country, while making his first forays into poetry. He worked at the Nigerian Tobacco Company, United Africa Company, the Fiditi Grammar School (where he taught Latin), and finally as Assistant Librarian at the University of Nigeria in Nsukka, where he helped to found the African Authors Association.
During those years, he began publishing his work in various journals, notably Black Orpheus, a literary journal intended to bring together the best works of African and African American writers. While his poetry can be read in part as powerful expression of postcolonial African nationalism, he was adamantly opposed to Negritude, which he denounced as a romantic pursuit of the "mystique of blackness" for its own sake; he similarly rejected the conception of a commonality of experience between Africans and black Americans, a stark philosophical contrast to the editorial policy of Black Orpheus. It was on precisely these grounds that he rejected the first prize in African poetry awarded to him at the 1965 Festival of Negro Arts in Dakar, declaring that there is no such thing as a Negro or black poet.
In 1963, he left Nsukka to assume the position of West African Representative of Cambridge University Press at Ibadan, a position affording the opportunity to travel frequently to the United Kingdom, where he attracted further attention. At Ibadan, he became an active member of the Mbari literary club, and completed, composed or published the works of his mature years, including "Limits" (1964), "Silences" (1962–65), "Lament of the Masks" (commemorating the centenary of the birth of W. B. Yeats in the forms of a Yoruba praise poem, 1964), "Dance of the Painted Maidens" (commemorating the 1964 birth of his daughter, Obiageli or Ibrahimat, whom he regarded as a reincarnation of his mother) and his final highly prophetic sequence, "Path of Thunder" (1965–67), which was published posthumously in 1971 with his magnum opus, Labyrinths, which incorporates the poems from the earlier collections.