FBI agent Malcolm Turner (MARTIN LAWRENCE), a master of disguises, and his behind the scenes and more straight-laced partner, John (PAUL GIAMATTI), have been assigned to track down Lester Vasgow (TERRENCE HOWARD), a convicted bank robber and recent prison escapee.
Since Lester's former girlfriend, Sherry Pierce (NIA LONG), has suddenly hit the road with her son Trent (JASCHA WASHINGTON) upon hearing of Lester's escape, and due to the fact that she's a previous suspect and bank employee who was neither charged nor cleared of being involved in the crime, the agents stake out the home of her Southern and rather large grandmother, Hattie May Pierce, affectionately known as "Big Momma" (ELLA MITCHELL).
When Big Momma suddenly leaves town to attend to a sick friend, the men decide to bug her house. Once inside, they get their big break when Sherry calls and leaves a message on the answering machine. Hearing that she's passing through and would like to drop in for a quick visit despite not getting along that well with her grandmother over the past several years, Malcolm picks up the phone and tries impersonating Big Momma so as to make Sherry stop by.
While not perfect, his impersonation works and he and John then set out - via a lifelike mask, wig, padding and extra-large clothes - to disguise Malcolm as Big Momma, hoping that Sherry will spill the beans to him/her about everything related to Lester and the robbery. Arriving at her grandma's house and having not seen her for several years, Sherry falls for Malcolm's impersonation, as do most of the woman's friends along with Ben (CARL WRIGHT), her older gentleman suitor.
Getting to know Sherry and Trent as both Big Momma and himself, Malcolm begins to fall for her and hopes that he can discover the truth about her involvement in the crime. With Lester zeroing in on Sherry and Trent, Malcolm and John continue their ruse of the former continuing to play Big Momma, all while dealing with an over ambitious security guard, Nolan (ANTHONY ANDERSON), and the worries that their cover will eventually be blown.