The daughter of working-class parents, McMillan grew up near Detroit. She was a graduate of the University of California at Berkeley (B.S., 1979) and Columbia University (M.F.A., 1979). She taught at the universities of Wyoming (1987–90) and Arizona (1990–92).

In McMillan's first novel, Mama (1987), a black woman manages to raise five children alone after she forces her drunken husband to leave. Disappearing Acts (1989) concerns two dissimilar people who begin an intimate relationship. Waiting to Exhale (1992; film, 1995) follows four black middle-class women, each of whom is looking for the love of a worthy man. The book's wild popularity helped the author secure a $6 million publishing contract for her fourth novel, How Stella Got Her Groove Back (1996), about a wealthy black woman of middle age who falls in love with a young cook while vacationing in Jamaica. McMillan edited Breaking Ice: An Anthology of Contemporary African-American Fiction (1990).