Danny Ocean's (George Clooney) crew gather around a hospital bed where Reuben Tishkoff (Elliott Gould) lies after suffering a heart attack. A flashback to four weeks earlier shows Reuben meeting with Vegas' most hated businessman, Willy Bank (Al Pacino) on the construction site of their new hotel. After Reuben secures crucial deals for Bank, he is intimidated into giving up his part of the investment, a strategy often employed by the vindictive Bank in previous deals. The shock causes Reuben's heart attack.
The gang swears to take revenge on Bank by utterly ruining his hotel, "The Bank", on the night of its grand opening. They aim to rig the various games at the casino so the players will win instead of the house. Bank was forced to take some hostile investors onto his Board of Directors to open the hotel, and if the house does not make at least $500 million in the first quarter, Bank will be removed from the chairmanship of his own hotel. The team also wishes to destroy any chance of Bank's winning the prestigious Five Diamond Award, the highest distinction granted a hotel. All of Bank's other hotels have won this award, and he has purchased valuable diamond necklaces to commemorate the successes. He has already optimistically purchased a necklace for his new hotel as well.
The main problem they face now is the artificial intelligence security system which 'can not only think, but reason', Greco, for which they hire Roman Nagel (Eddie Izzard) to lend his technical expertise. Their only other problem is how to ensure that all the patrons of the casino leave the place after making their wins but before they can lose their money all over again. Roman reveals the system was designed by a former classmate of his, Greco Montgomery (Julian Sands) and that it's designed to monitor all gamblers' psychological responses upon winning to make sure that they weren't expecting it (indicating a legitimate win). The only way to bypass it is by a huge natural disaster or a magnetron. If the system senses any trouble, it will automatically lock down, and rebooting would take three minutes twenty-one seconds. They rent a large tunnel boring machine, so it will induce an artificial earthquake underneath the hotel by generating the same resonance as the building. This is supposedly the drill that dug the Channel Tunnel from the British side.
Rusty (Brad Pitt) and Danny set about polluting a hotel room with biochemicals and bedbugs. In the lobby, a disguised Saul (Carl Reiner) is in line to check in. He "accidentally" drops a Five Diamond Award folder, catching the attention of Bank's aide, Abigail (Ellen Barkin), who immediately rushes to assist Saul. In line behind them, the genuine Five Diamond Award reviewer (David Paymer), who is supposed to be anonymous, is rudely jolted and then given the chemical-treated room by a bribed clerk. For the rest of his stay, the team ensures that he is treated as if he were an unwanted guest at a one-star hotel — he is not able to eat at the best restaurant so that the team can feed him a contaminated dumpling in the Chinese Restaurant (that gives him food poisoning), has his room filled with a noxious smell, gains multiple rashes from bedbugs, and is finally evicted from the hotel early by brutish security guards (Virgil and Turk in disguise). Before he leaves, the unhappy reviewer confronts Bank without revealing his identity and walks off.
Virgil Malloy (Casey Affleck) is sent to a Mexican factory to make the rigged dice. Upset by the terrible working conditions at the factory, he leads the workers on strike for better pay. The team sends Virgil's brother Turk (Scott Caan) to get the factory running again, but instead Turk joins the strike. The team eventually pay the factory workers their requested raise ($36,000 for the entire labor force, amounting to a $3.50 per week increase) and the factory reopens.
Disaster strikes when the drill intended to simulate the earthquake breaks down. As the replacement drill (the one that dug the Channel Tunnel from the French side) is only available for purchase and exceeds their budget, they have no choice but to make a deal with their old enemy Terry Benedict (Andy Garcia) for funding; Benedict claims he has a rivalry with Bank because Bank's new hotel is blocking his pool from sunlight. Benedict requests that, in return for his financial aid, they double his investment plus steal the diamond necklaces that Bank has purchased in expectation of his Five Diamond accreditation; Ocean, Rusty and Linus reluctantly agree. Soon after, Benedict even plays along with the plan when he coerces Banks into buying a rigged domino table, run by Frank (Bernie Mac), posing as a domino dealer. The diamonds are housed in a glass case in the penthouse and are worth $250 million collectively.
Yen (Shaobo Qin) is introduced as Mr. Weng, a high-roller and rich businessman, and Linus (Matt Damon), disguised with a distinctive nose, as his business manager. Yen the acrobat infiltrates the elevator shafts and air conditioning ducts and discovers that accessing the diamonds from the floor or ceiling will be borderline impossible. The new plan to access the diamonds is for the disguised Linus to seduce Abigail, who has access to the room with the diamonds. When opening night arrives, Linus uses pheromones to seduce her, leading him to the diamond room for privacy. Inside, he inconspicuously places small explosives around the base of the column containing the jewels.
Downstairs, the FBI enters and arrests Livingston (Eddie Jemison), as he has been caught rigging machines. An agent (Bob Einstein) tells Bank that a new set of machines will be coming in shortly. Roman then brings in the rigged machines, putting them in place of the genuine machines. Prints on the machine are matched with Livingston’s, and the casino comes up with a list of known associates- Ocean's Eleven. The list, with pictures, is downloaded to the computer in Bank's office. Basher (Don Cheadle), dressed up as the stunt man for the hotel's opening show that evening, distracts Bank from the computer while Virgil and Turk modify the downloaded names and faces so that the team's cover is preserved.
The infiltrated dice from Turk and Virgil's Mexican factory are distributed throughout the casino. When the team activates their equipment, disguised as Zippo lighters, the dice will flip and stop, manipulating the outcomes of games. Also, a slot is rigged to pay a huge progressive, and Rusty leaves the final dollar coin for the next person who trips the win (since the monitoring system is still active at this point).
With the drill turned on, a mock earthquake begins and Bank rushes to the Greco system. His tampered mobile phone acts as a magnetron, shutting down Greco for three minutes. Bank is trapped in the security office and the rigged games can now be played. Team members in the casino, including Danny, Rusty, Saul, Yen, Frank, and a recovered Reuben, all make sure that everyone who plays at the casino wins, so the casino pays out millions. When the system reactivates, a stronger earthquake is simulated, prompting everyone in the casino to cash in their chips and evacuate, taking away all the money with them.
Upstairs, the FBI agent disrupts Linus and Abigail, revealing Linus was using her to steal the diamonds and replace them with replicas. As Linus is then taken away, the agent is revealed to be his successful criminal father, who is also in on the scheme. As the two reach the helipad to leave, Francois Toulour (Vincent Cassel), alias "the Night Fox" (the antagonist from Ocean's Twelve), reveals himself, after following the whole crew from the start in a partnership with Benedict. Held at gunpoint from Toulour, Linus hands over the diamonds. Toulour throws him the gun, which is revealed to be empty, then base-jumps off the casino roof.
Basher lands the helicopter, and the team detonates the explosives, freeing the diamond case from the floor. The helicopter takes off, detaching the glass case carrying the real diamonds from the building. It is revealed that Linus never switched the diamonds. Danny confronts Bank, who has lost a total of $500 million dollars from the whole ordeal, not including the necklaces, telling him he broke the rules and needed to learn from what he's done; he also states that Bank obviously isn't going to go to the police and that there's no point in Bank threatening him, because all the people Bank could hire to destroy Danny like Danny more than Bank. As the helicopter flies off, an aghast Bank watches shell shocked. As Francois also witnesses this, he discovers his set of diamonds are fake and throws them away.
The team celebrates as the fireworks Bank had organized go off on the stroke of midnight, and Reuben is given the deed to 4.6 acres of land on the Las Vegas Strip. Danny pays a final visit to Benedict, chiding him for his trickery, telling him they were aware of Toulour's presence and informing him that the 72 million dollars promised to Benedict had been donated in Benedict's name to the children's charity "Camp to Belong".
Danny, Rusty, and Linus meet at McCarran airport and watch Benedict being featured on The Oprah Winfrey Show- a reference to a previous scene in which Rusty finds Ocean in his apartment watching the show and crying- for his apparent generous donation, before going their separate ways. Before leaving the airport, Rusty sits down to play a game of slots presumably rigged by Livingston. After rigging the machine to deliver a progressive jackpot on the next play, Rusty gives his seat at the machine to the beleaguered hotel reviewer. Rusty smiles as he walks away, hearing the man scream that he had won the $11 million jackpot as everyone crowds around him and cheers. This is alluded to earlier when several characters are debating how much money they would need to be paid in order to suffer as the reviewer did.