Mosley attended Goddard College and Johnson State College, and he became a computer programmer before publishing his first novel, Devil in a Blue Dress (1990; film 1995). Set in 1948, the novel introduces Ezekiel (“Easy”) Rawlins, an unwilling amateur detective from the Watts section of Los Angeles. It presents period issues of race relations and mores as the unemployed Rawlins is hired to find a white woman who frequents jazz clubs in black districts.

In all his Easy Rawlins novels, Mosley used period detail and slang to create authentic settings and characters, especially the earnest, complex main character, who continually is faced with personal, social, and moral dilemmas. In A Red Death (1991), set during the McCarthy era, Rawlins is blackmailed by the FBI into spying on a labour union organizer. In White Butterfly (1992) the police call on Rawlins to help investigate the vicious murders of four young women—three black and one white. Other novels featuring Rawlins include Black Betty (1994) and A Little Yellow Dog (1996). For the publication of Gone Fishin' (1997), a prequel to Devil in a Blue Dress, Mosley chose a small independent black publisher, Black Classic Press, over his longtime publisher W.W. Norton. The series continued with Bad Boy Brawly Brown (2002), Little Scarlet (2004), Cinnamon Kiss (2005), and Blonde Faith (2007).

Mosley's other novels include RL's Dream (1995), the story of a dying former blues guitarist (based on Robert Johnson (Johnson, Robert)) who is befriended by a young woman, and The Man in My Basement (2004), an examination of wealth, power, manipulation, and shifting relationships. Always Outnumbered, Always Outgunned (1997; filmed as Always Outnumbered for television, 1998), a collection of stories set in contemporary Watts, features the ex-convict Socrates Fortlow. Mosley returned to the Fortlow character in the stories of Walkin' the Dog (1999). In 2001 he returned to the mystery genre with the publication of Fearless Jones, introducing the title character and bookseller Paris Minton. In this book and its sequel, Fear Itself (2003), Mosley revisited the setting of Los Angeles in the 1950s. In 2008 he published Diablerie, a novel about a reformed alcoholic who confronts a violent secret from his past.

Mosley also tried his hand at other genres. He essayed science fiction in Blue Light (1998) and Futureland (2001), a group of interlocking stories, and nonfiction in Workin' on the Chain Gang: Shaking Off the Dead Hand of History (2000) and What Next: A Memoir Toward World Peace (2003).