The group started in 1991 in Memphis with DJ Paul (Paul Beauregard), Juicy J (Jordan Houston) and Lord Infamous (Ricky Dunigan). The original name for the hip hop group was "Backyard Posse". The group formed through the release of numerous EPs from their own record company with Nick Scarfo, Prophet Entertainment, which were sold around Memphis and the Mid-South. Later DJ Paul and Juicy J formed their own label, Hypnotize Minds Records. During their early career, they also propelled the careers of several other rappers. Eventually added before the release of Mystic Stylez were rappers Koopsta Knicca (Robert Cooper), Gangsta Boo (Lola Mitchell), and Crunchy Black (Darnell Carlton).
The group's membership varied from album to album, with the one constant being the duo of Juicy J and DJ Paul, who are producers as well as rappers. Other notable Mafia affiliates at one time or another include Crunchy Black, Gangsta Boo, Lord Infamous, Koopsta Knicca, La Chat, T-Rock, Project Pat, Lil Wyte, Killa Klan Kaze, and Indo G. The production acumen of Juicy and Paul also brought about a number of side projects (Tear da Club Up Thugs, Hypnotize Camp Posse, Da Headbussaz) and independent label ventures; the guys initially did business as Prophet Entertainment, later as Hypnotize Minds, working out deals with Relativity Records, Loud Records, and Columbia - all in turn.
At this point in the group's evolution, having signed to a major label and having scored an admirable hit single, group leaders DJ Paul and Juicy J began extending their brand. They started by releasing group member solo albums (Gangsta Boo, Koopsta Knicca), non-group member solo albums (Killa Klan Kaze) and also compilation-styled albums (Tear Da Club Up Thugs, Hypnotize Camp Posse, Da Headbussaz, and Prophet Posse). Around this time, they also released collections of tracks from earlier years (Underground Vol. 1: (1991-1994), Underground Vol. 2: Club Memphis, Underground Vol. 3: Kings of Memphis).


On March 5, 2006, Three Six Mafia made history as they became the first black music group to win an Academy Award for Best Song (the first black artist to do so was Isaac Hayes for Theme from Shaft in 1971) and also became the first hip hop artists to ever perform at the ceremony. The group was nominated for the song "It's Hard out Here for a Pimp" from the Hustle & Flow soundtrack. Three Six Mafia were credited by their real names, Jordan Houston (Juicy J) and Paul Beauregard (DJ Paul), along with two new group members, Darnell Carlton (Crunchy Black),and Taylor D (TD) and label mate Cedric Duane Coleman (Frayser Boy), although host Jon Stewart did refer to them as "Triple Six Mafia" after their victory, saying "To recap, Triple Six Mafia: 1. Martin Scorsese: 0." Scorsese would finally receive his own Oscar, for Best Director, the following year.