In contrast to the previous film, subplots which are centered on his parents (with his brother and grandmother, providing comic relief) occupy a substantial part of the film. Like the first film, the sequel's theme song is "Macho Man" by The Village People, which this time is played during the end credits.
After finding success with a DNA restructuring formula in the first film, Sherman Klump has created another formula which enables those who take it to find the Fountain of Youth. He has also met and fallen in love with a colleague, Denise Gaines, who has developed a method to isolate genetic material and later becomes his fiancée. Together, their work has enabled Wellman College to receive a $150 million award from a pharmaceutical firm to the excitement of Dean Richmond. Despite his good fortune, Sherman has a major problem: the personality of his vanquished alter ego, Buddy Love, is still ingrained inside him and causes him to act out in the same crass manner Buddy does.
After a few particularly unpleasant incidents, from Buddy kicking in, when Sherman sexually insults his own therapist trying to help him with it, then does the same thing to a woman walking a dog, and later during a toast turns around and reveals that his father was fired rather than retired, and then when Sherman intended on proposing to Denise, but then Buddy kicks in and makes it a perverted sex request, causing Denise to become mortified against him. Sherman heads to his lab where he uses Denise's methodology to isolate and remove the gene in Sherman's DNA where Buddy has manifested.
Determined to be rid of Buddy permanently, and despite of Jason warning him of potentially catastrophic consequences for his health, Sherman extracts the gene with from inside his body. However, he does not dispose of the genetic material and as a result, Buddy becomes a sentient being when a hair from a Basset Hound who was Sherman's test subject finds its way into it and causes such a reaction. To make matters worse, Jason's suspicions prove correct when Sherman discovers that, due to the extraction, his brain cells are beginning to deteriorate.
Realizing he needs to keep the youth formula out of Buddy's hands, Sherman stashes it at his parents' house. Buddy, who is trying to sell the formula to a different company, quickly realizes where it is and steals some of it. Buddy also doctors the remainder with fertilizer, which causes chaos at a demonstration the next day when a hamster Sherman uses to demonstrate the youth finding effects instead mutates and becomes an aggressive monster who violates Dean Richmond in front of a live television audience. The humiliated Dean fires Sherman, who learns that his brain's deterioration has worsened from Jason. Sherman then decides to end his engagement and break up with Denise.
In a last-ditch effort to secure the money, Sherman quickly works on a newer, much more potent formula while his mental faculties allow him to. While he is doing this, Richmond confronts him about Buddy's actions believing the two are working together. He leaves with Richmond and a tennis ball and head to the competing firm. Meanwhile, a worried Denise discovers what has happened and that Sherman's brain damage has progressed to almost eighty percent. Enlisting the help of Sherman's father Cletus, Denise heads for the firm Buddy is selling the formula to.
There, Sherman sets his plan into motion. Taking advantage of the canine DNA that crossed with Buddy's, Sherman uses the tennis ball to play fetch. The ball is covered with the new formula, which takes Buddy back to an infantile state and eventually to a glowing mass of genetic material. The idea is for Sherman to suck the genetic material back into his body through a straw, thus putting his DNA back together and returning him to normal. However, as Sherman is chasing what is left of Buddy, the glowing mass evaporates and thus Sherman cannot restore his intelligence.
Denise and Cletus arrive too late to save him, and seeing what has happened to Sherman, Denise breaks into tears. As they go to leave, Sherman takes a look at a fountain in the lobby of the building and remarks that it is "pretty". Seeing that the water is glowing, Denise realizes that the genetic material has reconstituted and that if Sherman drinks the water before it dissipates, he will be restored to normal. Although reluctant at first, Sherman drinks two handfuls of the water from Denise's hand then Cletus dunks Sherman's head under the water to drink, and thus he is able to get his genetic makeup back in proper order.
The film closes with Denise and Sherman's wedding reception, with Buddy nowhere to be found, Dean rehires Sherman with a wedding present and the hamster is back to normal and Dean decides to love the hamster.
The film grossed over $42.5 million in its opening weekend and went on to a total gross of over $123.3 million. It garnered an additional $43 million in foreign markets.
Unlike the first film, Nutty Professor II received negative reviews from critics. Adjectives such as "obnoxious", "lowbrow", "bloated", and "unfunny" cropped up frequently in reviews. Rotten Tomatoes lists the movie at a 26% approval rating, with the site's consensus stating that "While Eddie Murphy is still hilarious as the entire Klump family, the movie falls apart because of uneven pacing, a poor script, and skits that rely on being gross rather than funny." Salon.com's reviewer gave the movie one of its few positive notices, and offered the praise "cheerfully vulgar".
The New Yorker's Anthony Lane was particularly severe; in addition to hating the film, he dismissed Murphy's playing of multiple characters as "minstrelling", and charged the actor with "at once feeding us what we like and despising us for swallowing it." Most critics, however, mixed a generally negative assessment of the movie with at least a nod towards Murphy's versatility and comic talent.
Roger Ebert gave the film three stars, noting that while it was "raucous" and "scatological," the film overall proved to be "very funny" and "never less than amazing."