Professor Sherman Klump (EDDIE MURPHY) seems to have everything going for him. He has a great job working at Wellman University in their genome lab, he's about ready to pop the question to his girlfriend and fellow professor, Denise Gaines (JANET JACKSON), and he's just developed a successful age-regression concoction for which leading pharmaceutical companies are willing to pay top dollar.
The only problem is that he's never been able to shake his alter ego, Buddy Love (EDDIE MURPHY), who he accidentally created a few years back while trying to find a way to reprogram his DNA to help him lose weight. Although Sherman hasn't physically transformed into Buddy in some time, the obnoxious man hidden deep inside him is trying to cause problems, and he's generally succeeding.
To make matters worse, Sherman still finds himself embarrassed by his family -- including his grouchy father, Cletus "Papa" Klump (EDDIE MURPHY); his caring mother (EDDIE MURPHY); his libidinous Granny (EDDIE MURPHY); Ernie (EDDIE MURPHY), a cantankerous man; and nephew Ernie Jr. (JAMAL MIXON) -- and the way in which they act in front of Denise. They're tame compared to Buddy's repeated outbursts, however, so Sherman decides to rid himself once and for all of this troublemaker.
Performing an experimental genetic extraction, Sherman successfully removes Buddy. In doing so, however, he unknowingly sets into motion two serious repercussions. The first involves the fact that in altering his own genetic code, he's unknowingly created a progressively debilitating condition where his mental functioning begins to deteriorate.
Equally as bad, Buddy, through the help of a random dog hair, manages to physically manifest himself from a bottle of goo and appear once again as the fully anthropomorphic Buddy Love. As Sherman's intelligence continues to wane - much to the chagrin of Denise and Dean Richmond (LARRY MILLER), the latter who's counting on a big contract for their fountain of youth potion - Buddy then sets out to steal the formula and sell it as his own. With time running out as those situations escalate, Sherman tries to find a solution to both problems.