Young bachelors and best friends, Fred Flintstone (Mark Addy) and Barney Rubble (Stephen Baldwin) try to find decent girlfriends. They meet a little green alien called the Great Gazoo (Alan Cumming), who was exiled to Earth by his species. Gazoo, whom only Fred and Barney can see, decides to follow Fred and Barney to gather information, even though his superior knowledge and personality annoys them. Wilma Slaghoople (Kristen Johnston), meanwhile, is living in a mansion with her wealthy parents. Her control-freak mother, Pearl (Joan Collins), thinks that her daughter's wish to do common things such as bowling is silly and wants her to marry rich smooth casino-owner Chip Rockefeller (Thomas Gibson). After a fight with her mother, Wilma angrily storms out of the house and goes to a Bronto King in Bedrock, where she is waited on by Betty O'Shale (Jane Krakowski). Betty mistakenly thinks that Wilma is a "caveless" person and offers to share her apartment with her. Wilma is also given a job at the restaurant.
When Fred and Barney go to the restaurant for dinner, they are smitten with the girls and manage to talk them into going to a carnival with them. Fred goes with Betty and Barney goes with Wilma, but a lack of fizz between the two couples convince Fred and Barney to switch their dates. Wilma later takes Fred, Barney, and Betty to her father's (Harvey Korman) birthday party, where Fred intends on proposing to Wilma. Once they get there, they are all shocked to find out that Wilma comes from a very wealthy family, and Fred changes his mind about proposing to her after he meets Chip and realizes what he is up against. Although Pearl is against Wilma's new friends, Colonel Slaghoople is more accepting, simply glad that Wilma is happy, and in private gives her a pearl necklace that had once belonged to his mother. Fred and Barney humiliate themselves and Wilma at the dinner, but Wilma tells everyone that she is proud to be friends with them and they walk out of the mansion. Chip, however, devises a plan to get Wilma back by inviting the foursome to stay at his resort in Rock Vegas, believing that Fred will become caught up in gambling and Wilma will leave him.
The four of them enjoy the start of their trip. Chip gives them a huge comfortable suite at his resort, access to the pool, and spa treatment for Wilma and Betty. Fred decides to gamble, but never bets any high amount. Chip and his girlfriend Roxie (Alex Meneses) are visited by two men who reveal that Chip owes their boss a lot of money. Chip tells them that he will soon be married to Wilma and will use her family's money to pay off his debt, and Gazoo witnesses the entire conversation. Chip then invites Fred to play poker with the high rollers, and make more money, but Barney tries to prevent Fred from agreeing. Chip then tells Barney about the All-You-Can Eat buffet, and gets Roxie to seduce him into escorting her there.
Fred gets so caught up in gambling that he forgets that he and Barney were supposed to meet Wilma and Betty for dinner. While looking for Barney, Betty sees him wiping cream off of Roxie's chest and misinterprets that he is touching her breast. She begins crying and is approached by Mick Jagged (Cumming), who is attracted to her. She tells him that her boyfriend was cheating on her and he comforts her, then invites her to go out on a date with him, which she accepts. Fred and Wilma get into an argument over Fred's obsession with gambling and Wilma breaks up with him. Chip then arranges to have Fred lose all of the money he won so he will be left with nothing. Wilma runs into Chip and she tells him about her breakup with Fred. He then tells her that there have been burglaries around the hotel and should keep her pearls in a safe. Fred, who has lost all his money, goes to Chip for help, and Chip puts Wilma's pearls in Fred's pocket. He then announces to the entire resort that someone has stolen the pearls, and tells Fred to empty his pockets, and shows all of the guests that Fred has the pearls. Security arrests Fred, and Barney as well when he tries to help Fred. Wilma and Chip get back together.
While in prison, Fred and Barney are visited by Gazoo, who tells them about Chip's plan to use Wilma's wealth to pay his debt. They realize that Barney can slip through the bars and he steals the guard's keys and unlocks the cell. Meanwhile, Wilma and Betty think about their boyfriends and burst into tears. Fred and Barney disguise themselves as dancers and accidentally run into Jagged's dressing room. Barney tells Betty he loves her, and they get back together. Chip proposes to Wilma just as Jagged comes on stage to sing, but once he turns around, it is revealed to be Fred. He sings to Wilma, and she realizes that she still loves him. He comes off stage and confesses his love for her and proposes to her. She rejects Chip and agrees to marry Fred. Fred and Wilma get married in the Rock Vegas Chapel of Love, and upon the Pastor (John Stephenson) announcing them as man and wife, everyone sings "Meet the Flintstones". Mick Jagged sings "Viva Rock Vegas" at a party. Wilma throws back her bouquet of flowers and Betty catches it and looks at Barney with a smile on her face and they kiss. The newly married Fred and Wilma drive happily away with their friends and family waving them goodbye.
- Mark Addy as Fred Flintstone, a crane operator.
- Stephen Baldwin as Barney Rubble, a crane operator and Fred's best friend.
- Kristen Johnston as Wilma Slaghoople, the heir to the Slaghoople fortune.
- Jane Krakowski as Betty O'Shale, a waitress at Bronto King.
- Thomas Gibson as Chip Rockefeller, a casino owner who falls for Wilma.
- Alan Cumming as The Great Gazoo, an alien who befriends Fred and Barney.
- Alan Cumming also portrays Mick Jagged
- Harvey Korman as Colonel Slaghoople, the father of Wilma. Korman previously voiced the Great Gazoo in the original television series and the Dictabird in the first film
- Joan Collins as Pearl Slaghoople, the mother of Wilma.
- Alex Meneses as Roxie, the girlfriend of Chip who assists in his plot.
- Tony Longo as Big Rocko, a tough gangster that seeks to collect the money that Chip owes his unnamed boss.
- Danny Woodburn as Little Rocko, a short gangster of the mob that seeks to collect the money that Chip owes his unnamed boss.
- John Taylor as Keith Rockhard
- Irwin Keyes as Joe Rockhead; Keyes reprises his role from the first film
- Taylor Negron as Gazaam amd Gazing, aliens from Gazoo's race.
- Mel Blanc (archive footage, voice) as Puppy Dino; Blanc previously voiced Barney, Dino and numerous characters in the original series
- William Hanna (special appearance) as himself
- Joseph Barbera (special appearance) as himself
- John Stephenson as the Minister who marries Fred and Wilma.
- John Stephenson also voices the Showroom Announcer; Stephenson previously voiced a number of guest characters in the original series, most notably Mr. Slate and Count Rockula
- Rosie O'Donnell as the voice of the Octopus giving Wilma and Betty massages; O'Donnell previously portrayed Betty in the first film
- John Cho as Parking valet
- Kristen Stewart as Ring Toss Girl
- Jim Doughan as Dinosaur Confessor. Doughan previously portrayed a waiter in the first film.