Five years after socialite Ursula Stanhope left civilization to marry George of the Jungle, George finds himself hard-pressed to fulfill the roles of jungle king, father, and husband. George's stress level increases when the "Mean Lion" challenges him for leadership of the jungle, and when Ursula's mother Beatrice teams up with Ursula's ex-fiancé, Lyle, in a plot to forcibly take away all that George holds most dear.
To do this, Beatrice invites Ursula, George, and George Junior to visit Las Vegas, which they accept. Throughout the visit, Beatrice and some of Ursula's fellow socialites try constantly to convince Ursula that George is unworthy of her affection. George, observing the threats but not his wife's resistance, begins to think himself unworthy of Ursula.
During the same time, George's mentor Ape has become a gambler and is in debt to several creditors, including Lyle. Lyle, having learned that Ape does not possess the exploitation rights of Ape Mountain, engages Ape as a staged song performer and steals the deed from George's wardrobe. He thereafter sends agents who are called Sally and Kowalski to Ape Mountain, where they begin to demolish the jungle. The animals, terrified, turn to the Lion for guardianship.
Having failed to convince Ursula to divorce George, Beatrice hires a master of hypnosis to suppress Ursula's memory of having known George. The hypnotist suppresses the memory, replacing it with the idea that Ursula has married Lyle. George, upon learning of this, leaves his luck-charm with Ursula as she sleeps, then departs. He rescues Ape and leaves Las Vegas. Their departure triggers much commotion when the police force and the Animal Control Agency join forces to recapture them.
In San Francisco, Lyle fails to persuade Ursula that he is worthy of her affection. Ursula's memory, meanwhile, is stimulated by events similar to those in which George had played a major part.
Later, George then tries to reconnect with Ursula and George Junior before leaving to rescue the jungle. He has trouble convincing her that he is her husband. Knocking her unconscious, George continues his journey back home with her, Ape, George Junior, and Rocky the kangaroo. In the jungle, George overthrows the Mean Lion and tries to convince the other animals to join him in stopping the diggers, but fails in gaining their lost trust in him until the diggers become an immediate threat. George defeats the bulldozers with the help of George Junior, Ape, Shep, Rocky and Tookie Bird.
Lyle's agents Sally and Kowalski come to destroy the tree house, only to be defeated by George and Rocky. George is unable to defeat the digging machine until his son joins the fray. Lyle and Beatrice arrive to pick up Ursula and George Junior. George manages to defeat both of them by hanging Lyle in a tree and Beatrice is kissed by Ape. Lyle is angered by his defeat and insults the narrator voice, who replies by pulling him from the story's world. George kisses Ursula, restoring her full memory of him. They are subsequently re-married and learn to find balance among his duties.
- Christopher Showerman as George , King of the Jungle. He is portrayed as being less intelligent but well intentioned.
- Julie Benz as Ursula, Queen of the Jungle.
- Angus T. Jones as George Jr., Prince of the Jungle. George Jr. is a young boy trying to be like his dad.
- Thomas Haden Church as Lyle Van de Groot , George's arch enemy
- Christina Pickles as Beatrice Stanhope, Ursula's mother
- Marjean Holden as Sally, one of Lyle's hencwomen
- Erika Heynatz as Kowalski, another of Lyle's henchwomen
- John Cleese as Ape
- Michael Clarke Duncan as Mean Lion
- John Kassir as Rocky, Armando
- Keith Scott as Narrator
- Kevin Greutert as Tookie
- Kevin Michael Richardson as Grouchy Ape, Chimp
- Tress MacNeille as Tiger
- Dee Bradley Baker as Little Monkey, Water Buffalo
- John Cleese, Thomas Hayden Church, Keith Scott, and Kelly Miller are the only four actors who return for the sequel.
- Michael Clarke Duncan passed away on September 3rd, 2012 at age 54.