Landis dealt with several cases of historical significance during his career as a US federal judge. In 1907, he presided over a Standard Oil antitrust trial fining them $29 million for accepting rail freight rebates, although the verdict was later set aside. In 1918, he held the trial of a number of union leaders of the Industrial Workers of the World for violating the Espionage Act.
After his judicial career, Landis was the first Commissioner of Major League Baseball, serving from his election in November 1920 until his death in 1944. He is credited with restoring public confidence in the integrity of baseball following the 1919 Black Sox scandal. His detractors claim he perpetuated the color line and prolonged the segregation of organized baseball. He was elected to the Baseball Hall of Fame in 1944.