MIT student Ben Campbell, played by English actor Jim Sturgess, is accepted into Harvard Medical School, but he cannot afford the $300,000 tuition. He is interviewed as a potential candidate for the prestigious Robinson Scholarship, which will pay for all his school-related expenses. Despite boasting stats such as a 1590 SAT score, 44 MCAT score, and a 4.0 GPA at MIT, Campbell is told that competition for the scholarship is fierce. Ben is urged to write an essay that will make him stand out, an essay that will dazzle the recruiter and make Campbell's personality and abilities jump off the page.
During an advanced math class, Prof. Micky Rosa, played by Kevin Spacey, challenges Campbell with the Monty Hall problem, which Campbell solves successfully. Prof. Rosa invites Campbell to join his blackjack team led by Rosa, which consists of young men Choi and Fisher, and women Jill Taylor, played by Kate Bosworth, and Kianna. The system involves card counting, and the team is split into two groups: The "spotters", who play the minimum bet, keeping track of the count, and sending secret signals; and the "big players", who place large bets whenever the count at a table is favorable. Campbell is reluctant to join at first, but eventually relents, with the caveat that he will stay on the team only long enough to pay for his tuition. After weeks of intensive training, Campbell is given a final live test at an underground casino. He passes the test and is assigned to be a big player.
Prof. Rosa (sometimes referred to as "Micky") takes the team to Las Vegas where Campbell begins to realize the joys of a new lifestyle. Campbell's performance impresses Rosa, but eventually provokes jealousy in teammate Fisher. One evening, a drunken Fisher sits at Ben's table and starts talking about the "retard" in Rain Man, who won by counting cards. He then incites a melee when he spills a drink on another player at the table. Mr. Rosa kicks Fisher off the team and sends him home. All the while, security chief Cole Williams, played by Laurence Fishburne has been monitoring the blackjack team, especially Campbell. Campbell, meanwhile, falls for Jill, culminating in the pair sleeping together in Las Vegas.
Back at MIT, Campbell, because he is distracted by the blackjack, botches his part of a university project with his friends for the 2.0.9 competition. His friends angrily tell him that they will do the project themselves, with Campbell feeling that the project is not important anymore. On his next trip to Las Vegas, Campbell is emotionally distracted and continues playing even after he is signaled to walk away. An angry Micky Rosa storms out on the group, promising that Campbell will reimburse him for the $200,000 loss. Campbell and his three remaining teammates bankroll the rest of their money and agree to go into business for themselves. Micky, believed to have gone back to Boston, instead stays and rats out the M.I.T. team to casino security Cole Williams, who finds and apprehends Campbell and takes him to a secluded basement, where he beats him. Coleman releases Campbell with a threat and a dire warning.
Campbell returns to MIT only to find a letter telling him that he received an incomplete for one of his classes and therefore won't graduate. At the same time, he discovers that his winnings have been stolen from his dorm room. Campbell suspects that Micky Rosa is behind everything, but cannot prove it, so he makes Rosa an offer: Campbell and the team will hit Las Vegas for one final big score before the casino installs biometric software, as long as Rosa joins the team. Mr. Rosa agrees.
Dressed up in disguise, the team returns to Planet Hollywood's Vegas casino. They rake in over $640,000 before security chief Williams, along with a security team, finds them and gives chase. The team members quickly bag their chips and then flee through the casino. Ben has the bag of chips which he reluctantly gives over to Mickey as they decide to split up and meet later at the Foxx Strip Club. As the rest of the team is still being chased inside the casino, Mickey dives into a waiting limo and yells "airport" to the driver. It is obvious Mickey has no plans on going to the Foxx Strip Club. As he smiles with glee and dives into the bag of chips, he discovers the chips are actually hotel chocolates that are shaped just like casino chips. This is in part a reference to an earlier scene in the movie during which Choi shows his tendency to steal things by compulsively stealing a large number of hotel chocolates (the fake chips) from an unattended maid cart.
As the movie backtracks, we learn that Campbell and the rest of the team the whole time had a plan not only to make themselves a great deal of money but also to deliver Micky Rosa to Cole Williams. Early in the chase in the casino, Campbell and Jill get separated from Micky briefly, during which time Jill hands Ben the bag of chocolates as he hands her the bag of real casino chips, which she puts in her pocketbook. We also learn that security chief Cole Williams and Prof. Micky Rosa actually have a long history of playing cat and mouse in Las Vegas together. One night, while Cole was at his father's funeral, his casino got taken for seven figures. This event led to the firing of Cole and thus the grudge he holds against Micky.
It is revealed that Williams made a deal with Campbell: Williams would let Campbell come to Las Vegas for one last night to make a lot of money in exchange for Rosa. However, Williams, gun in hand, confronts Campbell on his way out and demands the bag of chips. Back in the casino, Williams informs Rosa that he also has a friend who is "good with numbers, but he works for the IRS."
The movie is told in the narrative voice-over POV of Ben Campbell. When Jill and Ben return to the casino, they not only meet the rest of the team, they also meet his two best friends from Boston with whom he had entered the 2.0.9. competition. Campbell says of them, "they were pretty good at basic math too." Campbell's summation is that getting his friends back, having really good life experiences, and hooking up with "the prettiest girl in school," were all worth much much more than all the money they had made counting cards. The movie closes with Campbell recounting the tale to the scholarship administrator, who looks back at him, "dazzled".