The film begins with an animated introduction featuring a plane heading toward "the Heart of Africa" (more specifically, a region called "Bukuvu"). The plane crashes and George, an infant, is lost, but enjoys vine swinging and crashing into trees as a running gag. Over 25 years later, George (Brendan Fraser) is a Tarzan-like man, the "King of the Jungle". His friends include a sophisticated talking gorilla named Ape (voiced by John Cleese), along with a toco toucan named Tookie; a small Capuchin monkey named Little Monkey; and an African elephant named Shep, whom he calls his "dog" (all voiced by Frank Welker).
The live action begins as heiress Ursula Stanhope (Leslie Mann) explores the jungle near George's home with the help of her guide, Mr. Kwame (Richard Roundtree) and some native porters. She has traveled to Africa alone, but she is joined by her wealthy fiance Lyle Van De Groot who has found her with the help of Max and Thor (Greg Cruttwell and Abraham Benrubi), two dopey poachers who are posing as trackers. That evening, Mr. Kwame recounts the legend of the White Ape, said to be a huge, super-strong primate who rules the surrounding jungle.
The next day, Lyle almost causes the death of one of the porters, and he abandons Ursula when the two of them are attacked by a lion. George saves Ursula and takes her to his treehouse home (albeit unconscious), and Lyle returns to the camp, claiming to have been attacked by the White Ape. While the exploration party searches for Ursula, George entertains her and teaches her to swing on vines. He also falls in love with her, so Ape advises him to woo her by making faces and beating his chest, as gorillas do. This fails to impress Ursula, but George wins her over with his charm, and they enjoy an evening of dancing around a campfire.
On the third day, the explorers discover George's treehouse, Lyle accidentally discharges his weapon and George gets shot in the arm (because the porters switched his pistol lighter for an actual gun) as George tries to prevent Max and Thor from shooting Ape with a tranquilizer gun. Seeing this happen, both Ape and Ursula scream in terror. While Lyle is arrested for the shooting (and called 'a big doofus' by the narrator), Ursula flies George to her home in San Francisco for medical treatment and buys clothes for him. George explores the city and saves a para-glider's life. With George's help, Ursula finds the courage to tell her parents that she no longer wants to marry Lyle, but her overbearing mother Beatrice Stanhope (Holland Taylor), who is intent on marrying her to a man of wealth and prestige, threatens George to give Ursula up or she would "remove his reason for wearing a loincloth".
Meanwhile, Max and Thor (who haven't left Africa, despite being deported) capture Ape, knowing that he can speak. Ape manages to send Tookie to San Francisco to ask George for help. When Tookie finds George, George returns to Africa to save Ape, and after realizing that she loves George, Ursula follows. George finds the poachers at the treehouse, with Ape in a cage, and he defeats them after an extended battle, though the two humiliate George in the process, twisting his nipples and violently tickle torturing him, much to George's pleasure. Noticing this, Thor keeps tickling the bound jungle man, who realizes Thor isn't stopping as the large man tickles him half to death, finally making George call out, "Stop it!"
Despite him begging for mercy, Thor refuses, tickling George closer to death. Before Thor can kill George with his tickling fingers, George eventually breaks free of Max's vice-like grip and prevails with help from Ursula and his animal family. However, Lyle appears and it looks like he is no longer in prison and has joined a marriage cult. He kidnaps Ursula with help from several mercenaries associated with the cult. Lyle intends to marry himself to Ursula immediately. After escaping the mercenaries with help from his gorilla friends, George chases Lyle and Ursula as they float into some river rapids on a raft. George makes a super fast swing that sends him crashing into a tree so hard that he groans "George don't feel so good." He then saves Ursula while Lyle enters a dark tunnel. After performing his wedding ceremony and exiting the tunnel, Lyle discovers that he has just married a gorilla. After professing their love for each other, George and Ursula have their wedding and ride off on Shep. They have a son and present him to the animals of the jungle on Pride Rock.
A little later, during the ending credits, Ape orders the credits to stop and reveals to the audience on his fate: he becomes a big singing star in Las Vegas. He is seen singing the Frank Sinatra song "My Way", with Thor and Max as background staff; they play as a coconut tree.
- Brendan Fraser as George, a strapping young man with long hair who was raised in the jungle like Tarzan and frequently crashes into trees while swinging on vines.
- Leslie Mann as Ursula Stanhope, a wealthy heiress
- Thomas Haden Church as Lyle van de Groot, Ursula's wealthy, despicable fiancé
- Richard Roundtree as Mr. Kwame, Ursula's jungle guide
- Greg Cruttwell as Max, a poacher and tracker that works for Lyle. He is the man who holds George still so Thor can meanly torture him by tickling him.
- Abraham Benrubi as Thor, a poacher and tracker that works for Lyle and wears black leather. He is the man that tickle tortures George.
- John Bennett Perry as Arthur Stanhope, Ursula's father
- Taylor Holland Taylor as Beatrice Stanhope, Ursula's mother
- Kelly Miller as Betsy, Ursula's friend
- Abdoulaye N'Gom as Kip, Ursula's friend and an African tour guide with Baleto and N'Dugo. He dislikes Lyle. He is the only tour guide with hair.
- Michael Chinyamurindi as N'Dugo, Ursula's friend and another African tour guide along with Kip and Baleto. He is slender. He dislikes Lyle.
- Lydell M. Cheshier as Baleto, Ursula's friend and the third African tour guide. He is stout and a bit Clumsy. He dislikes Lyle.
- John Cleese as Ape , a well-educated talking Gorilla. He later reveals to the audience (during the credits) that he became a major singing star.
- Keith Scott as Narrator
- Frank Welker as Lion, Little Monkey, Shep, Tooki Tooki Bird, and Gorilla sound effects
Gorilla Suit Performers
- Nameer Ed-Kadi - Ape (body)
- Tom Fisher
- Jody St. Michael
- Philip Tan
- Lief Tilden
- Robert Tygner - Ape (facial puppetry)
- The theme song was covered by the band The Presidents of the United States.
- The ending was a parody of The Lion King, which is also a Disney movie.