 Gary CooperHenry Louis 'Lou' Gehrig | Henry Louis 'Lou' Gehrig |
 Teresa WrightEleanor Twitchell | Eleanor Twitchell |
 Babe RuthBabe Ruth | Babe Ruth |
 Walter BrennanSam Blake | Sam Blake |
 Dan DuryeaHank Hanneman | Hank Hanneman |
 Elsa JanssenChristina 'Mom' Gehrig | Christina 'Mom' Gehrig |
 Ludwig StösselHenry 'Pop' Gehrig | Henry 'Pop' Gehrig |
 Virginia GilmoreMyra Tinsley | Myra Tinsley |
 Bill DickeyBill Dickey | Bill Dickey |
 Ernie AdamsMiller Huggins | Miller Huggins |
 Pierre WatkinMr. Twitchell | Mr. Twitchell |
 Harry HarveyJoe McCarthy | Joe McCarthy |
| BBob MeuselRobert W. Meusel (as Robert W. Meusel) | Robert W. Meusel (as Robert W. Meusel) |
| MMark KoenigMark Koenig | Mark Koenig |
| BBill SternBill Stern | Bill Stern |
 Addison RichardsCoach | Coach |
 Hardie AlbrightVan Tuyl | Van Tuyl |
 Edward FieldingClinic Doctor | Clinic Doctor |
 George LesseyMayor of New Rochelle | Mayor of New Rochelle |
 Edgar BarrierHospital Doctor | Hospital Doctor |
 Douglas CroftLou Gehrig as a Boy | Lou Gehrig as a Boy |
| GGene CollinsBilly (Age 8) | Billy (Age 8) |
 David HoltBilly (Age 17) | Billy (Age 17) |
 VelozSpecialty Dancer (as Veloz and Yolanda) | Specialty Dancer (as Veloz and Yolanda) |
| YYolandaSpecialty Dancer (as Veloz and Yolanda) | Specialty Dancer (as Veloz and Yolanda) |
| EEd AgrestiBarber (uncredited) | Barber (uncredited) |
| EErnie AlexanderBellhop with Flowers (uncredited) | Bellhop with Flowers (uncredited) |
 Hooper AtchleyLathered Man in Barber Shop (uncredited) | Lathered Man in Barber Shop (uncredited) |
 Edwin AugustRestaurant Patron (uncredited) | Restaurant Patron (uncredited) |
| BBettye AveryNightclub Singer (uncredited) | Nightclub Singer (uncredited) |
