Considering that his wife Sherri (NIA LONG) is expecting their first child together, FBI agent Malcolm Turner (MARTIN LAWRENCE) has given up field work and now does public relations for the agency, such as dressing up like Goldie the Safety Eagle for school kids. But when he hears that his first partner has just been murdered with that possibly being linked to a group of hackers planning to unleash their computer worm on government computers, he wants back in, but his boss refuses his request.
Learning that the agency is going to plant a nanny in the home of the chief suspect -- Tom Fuller (MARK MOSES) of National Agenda Software -- Malcolm gets an idea. Resurrecting the full-figured grandmotherly disguise he donned years earlier to nab a criminal, he dresses up as Hattie May Pierce, a.k.a. "Big Momma" and crashes the nanny interviews, thus displacing undercover agent Constance Stone (SARAH JOY BROWN) who was set to get the job.
With Tom having little time for his kids -- teenager Molly (KAT DENNINGS), younger sister and cheerleader wannabe Carrie (CHLOË GRACE MORETZ) and toddler Andrew (PRESTON SHORES & TREVOR SHORES) who's yet to say his first word -- Big Momma takes her orders, of which there are many, from his wife, Leah (EMILY PROCTER).
After the FBI eventually figures out Big Momma's real identity, they team Malcolm with FBI agent Kevin (ZACHARY LEVI) and computer whiz kid Stewart (JOSH FLITTER) in hopes that he'll find out who Tom's working with and thwart their plan. While doing that, he also sets out -- as Big Momma -- to help the Fuller kids with their various issues.