The unnamed "disease" that killed George Gipp wasn't a disease, it was actually complications from strep throat.
Mrs. Knute Rockne had approval over the casting and approved Pat O'Brien's make-up and acting without reservations.
Pat O'Brien's makeup--to make him look more like the real Knute Rockne, whom he did not resemble at all--took three hours each day to apply.
William Holden, John Wayne, Robert Young, and Robert Cummings were considered for the role of George Gipp, but only Dennis Morgan and Ronald Reagan tested for it, with Morgan having the edge until the last minute.
James Cagney, eager to break out of gangster roles, lobbied hard for the part of Knute Rockne. But Cagney had signed a petition in support of the anti-Catholic Republican government in the Spanish Civil War. Notre Dame had control over all aspects of the filming and would not okay Cagney for the role.