Babe Ruth missed several days of shooting and filming during the production because of his own illness.
In reality, Gary Cooper was decidedly not a fan of baseball and required extensive coaching in order to look even passable on a baseball diamond. In fact, he had never played the game before, even as a youth, and had never even seen a baseball game in person until he was hired for this film.
Samuel Goldwyn was initially reluctant about making the film as he believed that baseball movies were box office poison. He was persuaded to do it when he viewed footage of Gehrig's famous farewell speech.
Lou Gehrig's famous last speech is not delivered verbatim in the film; it was restructured slightly for dramatic emphasis.