Landis first became professionally involved with baseball in 1914, when he presided over the Federal League's injunction suit against the Major Leagues. So he was a natural man to go to after the 1919 Black Sox scandal broke out. He took the position on the condition that he be allowed to maintain his District judgeship in Illinois.

Set on maintaining the integrity of the game, Landis banned eight White Sox players involved in the scandal in one of his first acts as Commissioner. But these "eight men out" wouldn't be the only players to serve terms of banishment. Landis even banned Babe Ruth and Bob Muesel for 40 games due to unsanctioned barnstorming following the 1921 World Series.

Continually in poor health during his latter years, Landis died on November 25, 1944 at the age of 78.