Born as the eldest child 1 January 1915 in Union Springs, Alabama to sharecroppers John (Doctor) and Willie Ella (Mays) Clark. He renamed himself John Henrik (after rebel playwright Henrik Ibsen) and adding an "e" to his surname Clarke, as a symbol. Counter to his father's wishes for him to be a farmer, Clarke left Alabama in 1933 by freight train and went to Harlem, New York, where he pursued scholarship and activism.

In 1933 Harlem had drawn though Great Migration a concentration of African Americans, many of whom figured in the Harlem Renaissance. Clarke developed as a writer and lecturer during Great Depression years. He joined study circles like the Harlem History Club and the Harlem Writers' Workshop. He studied history and world literature at New York University, at Columbia University, and at the League for Professional Writers. He was an autodidact whose mentors included the scholar Arthur Schomburg. At the age of 78 Clarke obtained a doctorate from the then non-accredited Pacific Western University (now California Miramar University) in Los Angeles. The New York Times noted that Clarke's ascension to professor emeritus at Hunters College was "unusual...without benefit of a high school diploma." The Times also acknowledged that "nobody said Professor Clarke wasn't an academic original", but nonetheless referred to him using the honorific prefix "Mr." rather than "Dr.".

Prominent during the Black Power movement, Clarke advocated for studies on the African-American experience and the place of Africans in world history. He challenged academic historians and helped shift the way African history was studied and taught. Clarke was "a scholar devoted to redressing what he saw as a systematic and racist suppression and distortion of African history by traditional scholars." When some of the scholarship he championed was dismissed by many historians, Clarke imparted to them the biases of Eurocentric views.

"He devoted himself to placing people of African ancestry 'on the map of human geography'." He was quoted saying that "History is not everything, but it is a starting point. History is a clock that people use to tell their political and cultural time of day. It is a compass they use to find themselves on the map of human geography. It tells them where they are, but more importantly, what they must be."

Besides teaching at Hunter College and Cornell University, Clarke was active in creating professional associations to support the study of black culture. He was a founder and first president of the African Heritage Studies Association, which supported scholars in areas of history, culture, literature and the arts. He was a founding member of other organizations to recognize and support work in black culture: the Black Academy of Arts and Letters and the African-American Scholars' Council.

His writing included scholarly six books, many scholarly articles, and editing anthologies of black writing, a well as his own short stories, and more general interest articles. He was co-founder of the Harlem Quarterly (1949—51), book review editor of the Negro History Bulletin (1948—52), associate editor of the magazine Freedomways, and a feature writer for the Pittsburgh Courier and the Ghana Evening News.

Clarke had three children with his first wife, Eugenia Evans Clarke, a daughter who predeceased him, Lillie, and two surviving children, Nzingha Marie and Sonni Kojo.

At his death he was survived by his second wife Sybille Williams Clarke and his two children. He is buried in Green Acres Cemetery, Columbus, Georgia.

• 1985 - Faculty of the Africana Studies and Research Center at Cornell University named the John Henrik Clarke Library after him.

• 1995 - Carter G. Woodson Medallion, Association for the Study of Afro-American Life and History

• 2002 - Molefi Kete Asante listed Dr. John Henrik Clarke on his list of 100 Greatest African Americans.