A young Lou Gehrig finds himself at Columbia University studying engineering in an effort to follow in the footsteps of his Uncle Otto. It is the culmination of his mother's dreams for Lou. Lou, however, is also proficient at baseball and when his mother falls seriously ill, Lou (Gary Cooper) signs with the New York Yankees to play baseball professionally. After a stint in Hartford, he is called up to the big team. When first base man Wally Pipp is injured, Gehrig gets his chance to play and he begins a string of 2130 consecutive games. His mother gradually becomes resigned to Lou's new profession and becomes his greatest supporter. Lou meets an attractive young woman named Eleanor Twitchell (Teresa Wright) attending a game at Chicago's Comiskey Park and the two eventually fall in love, beginning a devoted eight-year relationship covering the last six years of Gehrig's baseball career and his two years suffering from a life-threatening illness.