Oakland Athletics general manager Billy Beane (Brad Pitt) is upset by his team's loss to the New York Yankees in the 2001 postseason. With the impending departure of star players Johnny Damon, Jason Giambi, and Jason Isringhausen to free agency, Beane attempts to devise a strategy for assembling a competitive team for 2002 but struggles to overcome Oakland's limited payroll. During a visit to the Cleveland Indians, Beane meets Peter Brand (Jonah Hill), a young Yale economics graduate with radical ideas about how to assess players' value. Beane tests Brand's theory by asking whether he would have drafted him (out of high school), Beane having been a Major League player before becoming general manager. Though scouts considered Beane a phenomenal player, his career in the Major Leagues was disappointing. After some prodding, Brand admits that he would not have drafted him until the ninth round and that Beane should probably have accepted a scholarship to Stanford instead. Sensing opportunity, Beane hires Brand as the Athletics' assistant general manager.
The team's scouts are first dismissive of and then hostile towards Brand's non-traditional sabermetric approach to scouting players, most notably Grady Fuson (Ken Medlock) – who is fired by Beane after insulting their approach, and takes to the radio airwaves and doubts the team's future. Rather than relying on the scouts' experience and intuition, Brand selects players based almost exclusively on their on-base percentage (OBP). By finding players with a high OBP but with characteristics that lead scouts to dismiss them, Brand assembles a team of undervalued players with far more potential than the A's hamstrung finances would otherwise allow. Despite vehement objections from the scouts, Beane supports Brand's theory and hires the players he selected, such as unorthodox submarine pitcher Chad Bradford (Casey Bond). Following the free agent signings, Beane finds that he also faces opposition from Art Howe (Philip Seymour Hoffman), the Athletics' manager. With tensions already high between them because of a contract dispute, Howe disregards Beane and Brand's strategy and plays the team in a traditional style despite their unsuitability. Beane eventually trades away the lone traditional first baseman, Carlos Peña, to force Howe to use the new recruits.
Early in the season, the Athletics fare poorly, leading critics within and outside the team to dismiss the new method as a dismal failure. Beane convinces the owner to stay the course, and eventually the team's record begins to improve. The Athletics go on to win 19 consecutive games, tying for the longest winning streak in American League history. Beane's young daughter implores him to go to the A's final game against the Kansas City Royals, where Oakland is already leading 11–0 after the third inning and appears set to advance their winning streak to a record-breaking 20. Like many baseball players, Beane is superstitious and avoids attending or sometimes even following games as they are in progress, but upon hearing how well the game is going on the radio, he decides to go. Beane arrives in the fourth inning, only to watch the team go to pieces and eventually allow the Royals to even the score at 11. Finally, the A's do win, on a walk-off home run by one of Brand's picks, Scott Hatteberg. Then, despite all their success in the second half of the season, the A's lose in the first round of the postseason, this time to the Minnesota Twins. Beane is disappointed, but satisfied at having demonstrated the value of his and Brand's methods. Beane is later approached by the owner of the Boston Red Sox, who realizes that the sabermetric model is the future of baseball, and offers to hire Beane as the general manager of the Red Sox. Beane passes up the opportunity to become the general manager of the Boston Red Sox, despite an offer of a $12.5 million salary, which would have made him the highest-paid general manager in sports history. He returns to Oakland to continue running the Athletics. In 2004, two years after adopting the sabermetric model, the Boston Red Sox win their first World Series since 1918.