In 1935, Walker received her Bachelor of Arts Degree from Northwestern University, and in 1936 she began work with the Federal Writers' Project under the Works Progress Administration. She was a member of the South Side Writers Group which included authors such as Richard Wright, Arna Bontemps, Fenton Johnson, Theodore Ward, and Frank Marshall Davis. In 1942, she received her master's degree in creative writing from the University of Iowa. In 1965, she returned to that school to earn her Ph.D.
Walker married Firnist Alexander in 1943; they had four children and lived in Mississippi. Walker was a literature professor at what is today Jackson State University (1949 to 1979). In 1968, Walker founded the Institute for the Study of History, Life, and Culture of Black People (now the Margaret Walker Center). In 1976, she went on to serve as the Institute's director.
Walker's poem For My People won the Yale Series of Younger Poets Competition in 1942 under the judgeship of editor Stephen Vincent Benet,. Her 1966 novel Jubilee, was based on her own great-grandmother's life as a slave.For My People was considered the “most important collection of poetry written by a participant in the Black Chicago Renaissance before Gwendolyn Brooks’s A Street in Bronzeville.” (Hines ) Richard Barksdale says “The poem was written when "world-wide pain, sorrow, and affliction were tangibly evident, and few could isolate the Black man's dilemma from humanity's dilemma during the depression years or during the war years." and that the power of resilience presented in the poem is a hope Walker holds out not only to black people, but to all people, to "all the Adams and Eves.”
Walker’s second novel, Jubilee, is the story of a slave family during and after the Civil War, and it took her thirty years to write. Roger Whitlow says that "It serves especially well as a response to white 'nostalgia' fiction about the antebellum and Reconstruction South."
In 1975, Walker released three albums of poetry on Folkways Records - Margaret Walker Alexander Reads Poems of Paul Laurence Dunbar and James Weldon Johnson and Langston Hughes; Margaret Walker Reads Margaret Walker and Langston Hughes; and The Poetry of Margaret Walker. In 1988, she sued Alex Haley, claiming his novel Roots: The Saga of an American Family had violated Jubilee's copyright. The case was dismissed. In 1991 she was sued by the widow of Richard Wright, whose biography she had published, on the grounds that her use of unpublished letters and an unpublished journal violated copyright. Wright v. Warner Books was dismissed by the district court, and this judgement was supported by the appeals court.