Ben Wrightman, a 7 year-old boy, is going to a Red Sox game with his Uncle Carl. His uncle treated him like a son because he had no children of his own. A narration explains that ever since that day, Ben became a die-hard Red Sox fan. Just about everything he owns bears the Red Sox name, emblem or the image of a Red Sox player (with the exception of his toilet paper, which bears the New York Yankees insignia). Ben inherited his uncle's season tickets when he died. The story picks up 23 years later with Ben (Jimmy Fallon) as a school teacher who is still rather immature for his age. He meets Lindsey Meeks (Drew Barrymore), a professionally successful workaholic executive. When he first asks her out, she rejects him, but she later changes her mind and agrees to go out with him.
On their first date, Ben finds Lindsey very sick. She has food poisoning from a new restaurant where she had dined at earlier during the day. Lindsey runs to her bathroom and vomits. Ben decides to stay over for the night and nurse her back to health as well as clean up her bathroom. The next morning, Lindsey, feeling better, finds Ben sleeping on her couch. Ben wakes up and he and Lindsey end up developing a romantic relationship with each other.
Overcoming her initial hesitance, she becomes attracted to him because of his ability to show a passionate commitment to something. That spring, he later pretends he is proposing to her, but instead asks her to the Red Sox home opener, where Stephen King (a longtime Sox fan) throws the first pitch. Lindsey attends, but not being a baseball or Red Sox fan, she knows nothing about the Curse of the Bambino or even how to pronounce the name Yastrzemski. The two continue to attend the games together until one summer night when Lindsey attempts to catch up on work by taking her laptop to the game. Not paying attention to the game, she is knocked out by a line drive foul ball by then Baltimore Orioles shortstop Miguel Tejada off Mike Myers. She eventually recovers, but stops going to the games.
Things take a turn for the worse when Lindsey invites Ben to go with her to Paris and he declines the offer because the Red Sox are in the heat of the playoff race. Before leaving for Paris, she tells Ben she is "late" and may be pregnant with his child, though they later learn she is not. Lindsey starts to become fed up with Ben's obsession with the Red Sox. Ben agrees to miss a game against the Yankees in order to go with Lindsey to her friend's birthday party. Ben and Lindsey have a wonderful time together, and after making love, he tells her it was one of the best nights of his life. Moments later, Ben receives a call from his ecstatic friend Troy who informs him that the Red Sox overcame a seven run deficit in the bottom of the ninth inning to pull off one of the greatest comebacks in team history. Ben becomes irate that he missed such a historic Red Sox moment, greatly hurting Lindsey's feelings. After Lindsey miserably declares he has broken her heart, he and Lindsey separate for a while.
Ben soon misses Lindsey, and visits her in a futile attempt to reconcile. He eventually feels her loss so deeply that he plans to sell his season tickets to Chris, Lindsey's girlfriend Robin's husband, in order to prove that she means more to him than the Red Sox do. Lindsey finds out about his plan during the celebration for her much-anticipated promotion. Immediately leaving the celebration, she rushes to the ballpark to try to stop him. She gets in during the 8th inning of the Red Sox—Yankees playoff game when the Sox are just 3 outs away from being swept. Ben is actually in the process of signing a contract with Chris as they sit in the stands. Because she is unable to reach Ben from her section in Fenway Park in time to stop him from signing the contract, she illegally runs across the field, deftly avoiding security personnel as she eventually reaches him. She tears Chris' contract in pieces and explains that if he loves her enough to sell his seats, then she loves him enough not to allow him to do so. The two reunite and kiss in front of the entire crowd.
The narration explains how the Red Sox won that game and then beat the Yankees three more times to win the American League pennant, later sweeping the National League champion St. Louis Cardinals in four games for their first World Series title in 86 years. Ben and Lindsay get married, and she gets pregnant. The narration explains that the baby will be named after one of the players, Ted Williams (for Ted Williams) if it's a boy and Carla Yastrzemski (for Carl Yastrzemski) if it's a girl, with the narration hoping for a boy.