In the summer of 1963, Frances "Baby" Houseman (Jennifer Grey) is vacationing with her affluent Jewish American family at Kellerman's, a family friendly resort in the Catskill Mountains. The younger of two daughters, Baby is planning to attend Mount Holyoke College to study the economics of underdeveloped countries and then enter the Peace Corps. She was named after Frances Perkins, the first woman in the U.S. Cabinet. Her father, Jake (Jerry Orbach), is the personal physician and friend of Max Kellerman (Jack Weston), the resort's owner. Baby is befriended by Max's smart aleck grandson Neil (Lonny Price).
In the Mediterranean Sea, Italian fishermen rescue an unconscious American man (Matt Damon) floating adrift with two gunshot wounds in his back. The boat's skipper finds a tiny laser projector surgically implanted under the man's skin at the hip. When activated, it displays the number of a safe deposit box in Zürich. When he regains consciousness, the man discovers he has dissociative (or psychogenic) amnesia. It is soon revealed the amnesia is selective, as the man realizes he knows several languages and advanced combat skills. Much later he remembers fragments of the C.I.A. trauma-based programming which erased and replaced his identity. When the ship docks, he sets off to investigate the deposit box.
Peter Highman (Robert Downey, Jr.) is on a plane, flying home to be with his wife Sarah (Michelle Monaghan), who is due to give birth. Sitting behind Peter is a man named Ethan Tremblay (Zach Galifianakis), who is going to LA to be an actor and is planning to scatter his recently deceased father's ashes at the Grand Canyon. When Ethan misuses the words "terrorist" and "bomb" while talking to Peter, they are both escorted off the plane. This is only the first of a series of misadventures caused by the drastically dysfunctional Ethan. Peter, now on the No Fly List and missing his wallet, agrees to drive with Ethan to Los Angeles.
The story begins with an adult Frank Walker telling an off-screen audience about his attendance at the 1964 New York World's Fair as a child. In the flashback, he meets David Nix, an official who is unimpressed with Frank's limited jet pack. Frank does draw the attention of a young girl named Athena. Seeing his potential, Athena gives Frank a pin embossed with a "T" symbol and tells him to follow her aboard the fair's "It's a Small World" attraction. Frank sneaks onto the ride, where his pin is scanned and he is transported into a futuristic cityscape known as Tomorrowland. He falls from a ledge, but straps on his jet pack and lands safely before Nix and Athena.
On docks outside Los Angeles, a semi-truck is loaded with electronics, but a corrupted dock worker informs an unknown person about the truck shipment. During the night, while the truck drives on the interstate, it is approached by three heavily modified black Honda Civics with green underglow. The occupants of the Civics immobilize the truck driver, hijack the truck and escape, passing through a roadblock and stealing thousands of dollars worth of shipment.
Tobey Marshall is a former race car driver who owns a Mount Kisco, New York garage, where he and his friends tune performance cars. Struggling to make ends meet, he and his crew participate in street races after hours. One day, Dino Brewster, Tobey's former rival, arrives at his garage in a Mercedes-Benz SLR McLaren with an offer to complete the build of a rare Ford Shelby Mustang worked on by the late Carroll Shelby. Dino wants Tobey and his crew to complete the project in exchange for 25% of the car's estimated selling price of $2 million. Despite objections from the crew, Tobey agrees to the deal.
College student Nick O'Bannon watches a race at McKinley Speedway for a study break with his girlfriend Lori Milligan, and their friends Janet Cunningham and Hunt Wynorski. While watching the race, Nick has a premonition that a race car crash will send debris into the stands, causing the stadium to collapse, and killing numerous people. When Nick panics, a fight breaks out, and several people leave before Nick's vision becomes a reality including Lori, Janet, Hunt; security guard George Lanter; mechanic Andy Kewzer; mother Samantha Lane; tow truck driver Carter Daniels; and Andy's girlfriend Nadia Monroy. Nadia gets angry and yells at them when she is suddenly obliterated by a stray tire that flies out of the stadium.
Michael Sullivan Sr. (Hanks) is an enforcer for Irish mob boss John Rooney (Newman) in Rock Island, Illinois during the Great Depression. Rooney raised the orphan Sullivan and loves him more than his own biological son, the unstable Connor (Craig). Connor snaps and kills disgruntled associate Finn McGovern when meeting him with Sullivan, resulting in Sullivan gunning down McGovern's men. Sullivan's twelve-year-old son Michael Sullivan, Jr had hidden in his father's car and witnesses the event. Despite Sullivan swearing his son to secrecy and Rooney pressuring Connor to apologize for the reckless action, Connor murders Sullivan's wife Annie and younger son Peter, mistaking him for Sullivan, Jr. He then sends Sullivan to an ambush at a speakeasy but Sullivan realizes and escapes to Chicago with his son to seek Al Capone, for work and to discover the location of Connor, who has gone into hiding.
On Fat Tuesday in New Orleans, the ferry Sen. Alvin T. Stumpf is carrying hundreds of U.S. Navy sailors and their families across the Mississippi River from their base to the city. Suddenly, the ferry explodes and sinks, killing 543 passengers and crew. Special Agent Doug Carlin (Denzel Washington) from the Bureau of Alcohol, Tobacco, Firearms and Explosives (BATF) is sent to investigate and discovers evidence of a bomb planted by a domestic terrorist. Arriving at the scene he hears his unique ring tone coming from a nearby body bag. He then meets with local investigators and FBI Special Agent Paul Pryzwarra (Val Kilmer), and informs them of his findings. He later learns about a charred body pulled from the river, identified as Claire Kuchever (Paula Patton). Unlike the other bodies from the ferry, though, this one appears to have been killed before the explosion.
Jerry Shaw (Shia LaBeouf) is a Stanford University dropout who learns his identical twin brother Ethan, a first lieutenant in the US Air Force, has been killed. Following the funeral, Jerry is surprised to find $750,000 in his bank account. Later he finds his Chicago apartment filled with weapons, ammonium nitrate, classified DOD documents, and forged passports. He receives a phone call from a woman (Julianne Moore) who warns that the FBI is about to arrest him and he needs to run.
John Bridger, a professional safecracker, has assembled a team to steal 35 million dollars worth of gold bullion from a safe held by Italian gangsters in Venice that had stolen it weeks earlier. The team includes Charlie Croker, a thief and John's protege, Napster, a computer expert, Rob, their wheelman, Steve, their inside man, and Left Ear, their explosives expert. They successfully complete the theft by stealing the actual safe and stealing the gold from it while the gangsters are occupied with a decoy. After leaving the city, the team agrees to split up the gold and part ways once they return to the United States. However, Steve turns on them: in the Alps near Austria, he and his own men intercept their van and take the gold, shoots and kills John, while the rest of the team falls into the river trying to escape.
Blue-collar mechanic Carter Chambers (Freeman) and billionaire hospital magnate Edward Cole (Nicholson) meet for the first time in the hospital after both have been diagnosed with terminal lung cancer. Although Edward is reluctant to share a room with Carter, complaining that he "looks half-dead already", they become friends as they undergo their respective treatments.
In 1984, Captain Ray Quick and Colonel Ned Trent, explosives experts working for the CIA, are on a mission to blow up a car transporting a South American drug dealer. But when the car appears, a little girl is inside with the dealer. Ray insists they abort the mission, but Ned intends to see it through and allows the explosion to happen, resulting in the deaths of both the drug dealer and the girl. Angered by the girl's wrongful death, Ray savagely beats Ned and flees, effectively resigning from the CIA.
Twenty years after the events of the first film, Lloyd Christmas has been committed at an insane asylum ever since his doomed romance with Mary Swanson. During a visit, Harry Dunne discovers that Lloyd pranked him into thinking he was mentally disturbed the entire time. Lloyd leaves with Harry and they head to their apartment, where Harry reveals one of his kidneys is bad and he needs a donor soon.
Brothers Walter and Gary, residents of Smalltown, are fans of the Muppets, having watched The Muppet Show throughout their youth. Now adults, Gary plans a vacation to Los Angeles with his girlfriend, Mary, to celebrate their tenth anniversary, inviting Walter so he can tour the Muppet Studios. Mary feels Gary's devotion to Walter is detracting from their relationship.