The story begins in 1902 in Baltimore, Maryland, where a seven-year-old Babe Ruth, troubled and not-so disciplined, is sent to the St. Mary's Industrial School for Boys, a reformatory and orphanage. Ruth is sent by his father, George Herman Ruth Sr. (Bob Swan), who cannot handle raising the boy. At the school, Ruth is schooled by Catholic missionaries and is made fun of by other children, because of his large size. Brother Matthias Boutlier (James Cromwell), the Head of Discipline at St. Mary's, first introduces Ruth to the game of baseball. During a session of batting practice, Ruth hits several towering home runs off of Matthias, who is pitching. Brother Matthias and others are stunned by Ruth's amazing power to drive the ball.
In 1932, the dawn of the Great Depression, a young baseball fan Yankee Irving (Jake T. Austin), whose father Stanley (Mandy Patinkin) works as a janitor for New York City's Yankee Stadium, dreams of playing for the Yankees but can't even play sandlot baseball well enough to avoid being picked last. One day beside the sandlot, he finds a talking baseball he names Screwie (Rob Reiner).
The story begins on "the strangest day" of Larry Burrows' (James Belushi) life (his 35th birthday) consisting of a series of comic and dramatic misadventures. Larry, who blames all of his life's problems on the fact that he struck out during a key moment of a high school baseball game on his 15th birthday, wishes he had done things differently. His wish is granted by a guardian angel-like figure named Mike (Michael Caine), and appears at various times as a bartender, a cab driver, and so on. Larry soon discovers that Mike has transferred Larry into an alternative reality in which he had won the pivotal high school game. He now finds himself rich and (within his company) powerful, and married to the boss' (Bill McCutcheon) sexy daughter Cindy Jo Bumpers (Rene Russo). At first, his new life seems perfect, but he soon begins to miss his best friend Clip Metzler (Jon Lovitz) and wife Ellen (Linda Hamilton) from his previous life; he also discovers that his alternate self has created many enemies, like Jewel Jagger (Courteney Cox), and as Larry's problems multiply, he finds himself wishing to be put back into his old life.
Billy Heywood (Luke Edwards) is a preteen son to a widowed single mom, Jenny (Ashley Crow), and a Little League Baseball player. Billy's grandfather is Thomas Heywood (Jason Robards), owner of the Minnesota Twins.
Kim Sang-nam (Jung Jae-young), a hot-tempered professional baseball player, is sent to the countryside to coach a team of hearing-impaired players in order to avoid media coverage of his recent involvement in an assault case. At first, Sang-nam has a difficult time imagining how he can teach baseball to a group of boys who can’t hear, but as he spends time with them he starts to believe that they can play the game. Motivated, Sang-nam decides to help them prepare for the nationals. As Sang-nam trains them, he forms bonds with the players, as well as with the music teacher and baseball manager Ms. Na (Yoo Sun). But things don’t go the way Kim plans and their difficulties communicating with one another exacerbates the situation.
Billy Wyatt (Harmon) was once a very talented high school baseball player and minor-league prospect. Now in his 30s, doing poorly financially and socially, he receives a telephone call from his mother revealing that Katie Chandler (Foster), his former child-sitter—and later, in his teens, his first love—has committed suicide. She has left a note specifying Billy as custodian of her ashes.
Small-time promoter/hustler Marvin Lazar (Curtis) sees a potential money-making venture in the Bears that will help him to pay off his debts. After seeing a TV spot about the Bears, he decides to chaperone the baseball team for a trip to Japan in their match against the country's best little league baseball team.
Coop (Trey Parker) and Remer (Matt Stone) are 23 and unemployed. They arrive uninvited at a party hosted by a former high school classmate of theirs. After finding out that their classmates have matured, Coop and Remer find themselves outside drinking beer and shooting hoops. Two former classmates challenge them to a game. The two see that their opponents are very good at basketball, so they say they will only play a new game they picked up "in the hood".
Deuce Cooper (Matt LeBlanc) is a farm boy who arrives at an open tryout for the Santa Rosa Rockets minor league baseball team. He makes the team after blowing away the scouts with his 'rocket' arm as well as having a strong training camp. Deuce also befriends a chimpanzee, 'Ed,' after being told he is his new roommate/teammate. After they move in to their apartment, Deuce develops a relationship with his neighbor, Lydia. Also, Ed becomes very close with her daughter, Elizabeth. Deuce's game really begins to take off as well as Ed's and the team becomes a league contender. Deuce's coach, Chubb, thinks Deuce can be an MLB starter if he keeps his head on straight. But after the owners sell Ed to make a buck, Deuce takes matters into his own hands and goes to find Ed only to see him being tortured by a pair of goons. Deuce saves Ed but Ed escapes and finds a truck of Frosted Bananas and doesn't realize he is stuck inside the trailer, which is ice cold. Ed ends up in the hospital from almost freezing to death before the final game of the season and Deuce questions his own ability to continue playing without his best friend. Deuce ends up playing and struggles right off the bat. But when Ed, Elizabeth and Lydia arrive at the game together, Deuce turns up the heat and the Rockets take the championship. Ed, Deuce, Lydia and Elizabeth then become a family and live happily ever after.
The 1919 Chicago White Sox are considered the greatest team in baseball and, in fact, one of the greatest ever assembled to that point. However, the team's owner, Charles Comiskey, is a skinflint with little inclination to reward his players for a spectacular season.
Texas farm boy Monty Stratton (Stewart) demonstrates a knack for throwing a baseball. He manages to get a tryout with the Chicago White Sox that is followed by a contract. A teammate introduces him to a young woman named Ethel (Allyson) and soon they are married and raising a family.
Take Me Out to the Ball Game is a period piece set in 1908. The plot revolves around a fictional American League team, the Wolves, and two of its players, Eddie O'Brien (Gene Kelly) and Dennis Ryan (Frank Sinatra), who are also part-time vaudevillians.
Chuck Murdock (Joshua Zuehlke), a 12-year-old boy from Montana and the son of a military jet pilot, becomes anxious after seeing a Minuteman missile on a school field trip, which is intensified by a nightmare of a fork dropping after being told that the speed and effectivess would be done "before a dropped fork hits the floor". Chuck protests the existence of nuclear weapons by refusing to play baseball, which results in the forfeit of a Little League game by his team.