The movie begins as Chicago Bears rookie running back Gale Sayers (Williams) arrives at team practice as an errant punt is sent to Sayers. Fellow rookie running back Brian Piccolo (Caan) goes to retrieve the ball, and Sayers flips it to him. Before Sayers meets with coach George Halas (Jack Warden) in his office, Piccolo tells him – as a prank – that Halas has a hearing problem, and Sayers acts strangely at the meeting. Sayers pranks him back by placing mashed potatoes on his seat while Piccolo is singing his alma mater’s fight song.
During practice, Piccolo struggles while Sayers shines. Sayers and Piccolo are placed as roommates, a rarity during the racial strife at the time. When they are placed together Brian is scared he didn’t make the team, and Gale makes a great point saying “if you didn’t make the team, we wouldn’t be placed together as roommates.” Their friendship flourishes, in football and in life, quickly extending to their wives, Joy Piccolo and Linda Sayers. Sayers quickly becomes a standout player, but he injures his knee in a game against the San Francisco 49ers. To aid in Sayers’s recovery, Piccolo brings a weight machine to his house. In Sayers’ place, Piccolo rushes for 160 yards in a 17–16 win over the Los Angeles Rams and is given the game ball. Piccolo challenges Sayers to a race across the park, where Sayers stumbles but wins. Piccolo wins the starting fullback position, meaning both he and Sayers will now be on the field together, and both excel in their roles.
Piccolo starts to lose weight and his performance declines, so he is sent to a hospital for a diagnosis. Soon after, Halas tells Sayers that Piccolo has cancer and will have part of a lung removed. In an emotional speech to his teammates, Sayers states that they will win the game for Piccolo and give him the game ball. When the players later visit the hospital, Piccolo teases them about losing the game, laughing that the line in the old movie wasn’t “let’s blow one for the Gipper.”
After a game against the St. Louis Cardinals, Sayers visits Joy, who reveals that Piccolo has to have another surgery for his tumor. After he is awarded the “George S. Halas Most Courageous Player Award”, Sayers dedicates his award to Piccolo, telling the crowd that they had selected the wrong person for the prize and saying, “I love Brian Piccolo, and I’d like all of you to love him, too. And tonight, when you hit your knees, please ask God to love him.” In a call, Sayers mentions that he gave Piccolo a pint of blood while he was in critical condition. Piccolo dies with his wife by his side. The movie ends with a flashback of Piccolo and Sayers running through the park, while Halas narrates that Piccolo died at age 26 and is remembered not for how he died but for how he lived.