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.
The unnamed "disease" that killed George Gipp wasn't a disease, it was actually complications from strep throat.
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.
In the scene where Rockne is in bed with phlebitis and his doctor is exiting the room, there is a framed photograph of the real Knute Rockne hanging on the wall.