Sisler was born on October 16, 1931, in St. Louis, Missouri, to George Sisler, a Baseball Hall of Fame player, and Kathleen. He played baseball and two other sports at John Burroughs School. When he was 16, he went to work for his father, a coach in the Brooklyn Dodgers organization, who allowed him to keep statistics and occasionally to pitch. The Dodgers did not pursue a contract with him, due in part to his commitment to Princeton University and future military obligation. He played baseball and basketball at Princeton, where in 1951, his earned-run average was 0.99.