Serote was born in Sophiatown, Johannesburg, South Africa, and went to school in Alexandra, Lesotho, and Soweto. He first became involved in the Black Consciousness Movement when he was finishing high school in Soweto. His presence in that town linked him to a group known as the "township" or "Soweto" poets, and his poems often expressed themes of political activism, the development of black identity, and violent images of revolt and resistance. He was arrested by the apartheid government under the Terrorism Act in June 1969 and spent nine months in solitary confinement, before being released without charge. He went to study in New York, obtaining a Fine Arts degree at Columbia University, before going to work in Gaborone, Botswana, and later London for the African National Congress in their Arts and Culture Department.
After contributing poems to various journals, in 1972 he published his first collection, Yakhal'Inkomo. It won the Ingrid Jonker Poetry Prize in 1973.
He was a Fulbright Scholar and received a fine arts degree from Columbia University in 1979. He was not able to return to South Africa and he began a life in exile, living in Botswana and London, where he was involved in the Medu Art Ensemble.