The gang is back! For the sequel to Eddie Murphy’s nutty and crazy professor movie, The Nutty Professor 2! In this movie we see Sherman getting ready to get married to none other than Michael Jackson’s sister! Janet Jackson stars in this hilarious comedy sequel.

Professor Sherman Klump has created a new de-aging formula. He is also in love with DNA researcher, Denise Gaines, developer of a method to isolate genetic material. Despite his good fortune, Sherman's id alter ego, Buddy Love, has taken to sporadically controlling Sherman's body. Sherman becomes determined to permanently rid himself of Buddy when his antics corrupt Sherman's attempted proposal to Denise into a mortifying display of perversion.

Despite his assistant, Jason, warning him of potential consequences, Sherman uses Denise's methodology to isolate and remove the DNA where Buddy has manifested. However, the Buddy genetic material grows into a sentient being when a hair from Jason's Basset Hound, Buster, accidentally lands in it. Sherman apologizes to Denise and they become engaged. Later, Dean Richmond informs them that Phleer Pharmaceuticals has offered Wellman College $150 million for the youth formula.

Sherman and Denise then encounter the newly reformed Buddy at a movie theater. Buddy pickpockets Sherman and learns of the $150 million offer. He subsequently visits the pharmaceutical company, making a rival bid of $149 million with Leanne Guilford, President of Acquisitions, for the youth formula. Sherman learns that the extraction has altered his body chemistry and that he is losing his intelligence. Realizing he needs to keep the youth formula out of Buddy's hands, Sherman stashes it at his parents' home.

Sherman's sexually frustrated father Cletus accidentally drinks some of the youth formula. He goes out for a night on the town and attempts to seduce his wife and Sherman's mother, Anna, but she is horrified. Buddy witnesses Cletus changing and realizes that the youth formula is being stored in the Klump household. Meanwhile, Sherman's condition causes him to act like a fool in front of Denise's parents, concerning her.

Buddy steals some of the youth formula from the Klump household, filling the vial the rest of the way with fertilizer. This sabotage causes chaos at a demonstration the next day as Petey, the male hamster Sherman uses to demonstrate the formula, mutates into a giant monster who rapes Richmond as he is trying to escape under a fur coat, as Petey confuses him for Molly, the female hamster that escaped during the event. The humiliated and enraged Richmond fires Sherman, who soon learns from Jason that his brain's deterioration has worsened, so he decides to break up with Denise.

Cletus consoles a depressed Sherman, and inadvertently gives him the solution to regaining his intelligence: getting Buddy Love back into his DNA.
Meanwhile, a worried Denise discovers what has happened and that Sherman's brain damage is progressing. With Cletus' help, Denise goes after him.

Sherman takes advantage of the canine DNA crossed with Buddy's and throws the tennis ball to distract him. Buddy catches the ball in his mouth, and the youth formula transforms him back into a glowing mass of sentient genetic material. Sherman chases the genetic material, intent on drinking it to correct his condition. However, it evaporates on the edge of a fountain before he can. Cletus and Denise arrive too late to save him, and Denise breaks into tears, which hit the genetic material and fall into the fountain.

As they go to leave, Sherman looks into the fountain, remarking that it is "pretty". Seeing the water is glowing, Denise realizes the genetic material has reconstituted thanks to her tears and that if Sherman drinks the fountain water, he will be restored to normal. When he drinks it, he is able to restore his intelligence. Sherman and Denise later get married, while Cletus and Anna reconcile with each other.