Janet Jackson as Denise Gaines replaces Sherman's girlfriend in the first film, Carla Purty, because the actress who played her, Jada Pinkett, left due to marrying Will Smith, her pregnancy, and later her signing on to the "Matrix" sequels. Carla Purty is mentioned to be just a friend.

Kathleen Freeman, who plays the nosy neighbor, was in the original The Nutty Professor (1963) as Millie Lemmon.

When Sherman runs into Buddy in the theater room , the movie showing is "Cape Fear" (1962).

Eddie Murphy has eight character credits to his name: Sherman Klump, Ernie Klump, Mama Klump, Papa (Cletus) Klump, Younger Cletus, Grandma, Lance Perkins, and Buddy Love. To date, this is the most characters in a single movie for Murphy, beating his previous record of seven characters for the first "Nutty Professor" film (although one can argue that he still only portrays seven characters in this film, since one character is just a younger version of another.).

Larry Miller improvised the operatic note during the scene where his character comically gets violated by Petey the Giant Hamster. As shown in the film's trailer, Dean Richmond singing "Guy!" originally wasn't going to make it into the final film.