Following the Rugrats' joint family vacation in Paris and the Blackburns' apprehension, they go on an imaginary safari, with Tommy impersonating Nigel Thornberry, whom he idolizes, and spoofing his nature show. The babies and their families are about to go on vacation on a tropical cruise ship, courtesy of Tommy's father, Stu. Upon arriving at the pier to depart, they discover that he has instead rented a ramshackle boat as their real vacation. The families are angered that Stu did not consult them on his plans, and during their journey, the boat is flipped over by a rogue wave during a tropical storm. Everyone is forced to abandon the ship and board a life raft as the ship sinks, and the group blames Stu.
The next morning, they arrive on a small, seemingly uninhabited island in the South China Sea. The grown-ups nominate Betty as leader after Didi forbids Stu from volunteering. On the opposite side of the island is the famous globe-trotting family, the Thornberrys, out to film a clouded leopard. The kids, except for Angelica, set off to find Nigel to get his help to get them home, as they suspect he is somewhere on the island. Along the way, Chuckie gets lost and runs into Donnie Thornberry, who steals his clothes, forcing Chuckie to wear Donnie's shorts.
Meanwhile, Eliza Thornberry is exploring the jungle with Darwin, her pet chimpanzee, and runs into Spike, the Pickles' dog. Since Eliza can talk to animals, Spike is heard speaking; he informs her that his babies are lost somewhere on the island. Under the impression that Spike means he is looking for puppies, Eliza and a reluctant Darwin agree to help him find them. Following a close encounter with Siri, an angry clouded leopard, they learn that he meant human babies.
Simultaneously, Nigel finds the lost babies. He heads in their direction but ends up tumbling down a hill and suffers amnesia after a coconut falls on his head, which reverts him to his three-year-old self. They encounter Siri, but Donnie fends her off; Chuckie finds him and they swap back their clothes. After escaping from Siri on a high-speed pram, the gang lands in a crater. Angelica runs into Debbie Thornberry, and takes off with Debbie in the Thornberry's all-purpose mobile communication vehicle (commvee). To get back more quickly, Angelica steals the Thornberry's bathysphere and accidentally sinks the commvee in her attempt to pilot it. She manages to find and retrieve the babies and Nigel.
Meanwhile, Stu has managed to create a working coconut radio. He and the other parents run into Donnie. After chasing him down the beach, they run into Marianne Thornberry. Stu's coconut radio picks up the babies, as Angelica accidentally turned on the bathysphere's radio. Angelica and Susie, while fighting for control, crash the bathysphere at the bottom of the ocean. Nigel hits his head in the crash and reverts to his normal self. Stu comes up with a plan to raise the commvee, and Marianne then uses the automatic-retrieval system to rescue Nigel and the babies just as the air runs out.
The babies and Nigel are reunited with their respective families, with Stu being thanked and forgiven, and everyone gets on board the cruise they had wanted originally. The Thornberrys join them, too, deciding that they should take a vacation, much to Debbie's delight, and Spike vows never to lose his babies again.
The film grossed $39 million in the United States and $16 million internationally for a worldwide total of $55 million against a production budget of $25 million. The film opened at #4 behind Finding Nemo, 2 Fast 2 Furious, and Bruce Almighty.
Charlotte Pickles: Oh, and, Johathan, don`t think that just because I'm on a luxury Lipschitz cruise in the South China Seas I won't be checking messages, E-mailing, and carrier pigeons on the hour.
Chaz Finster: I can't believe you did this without consulting us, Stu. Look at poor Kira. [gestures to Kira, who is suffering from severe seasickness] This was supposed to be our honeymoon.