Hanlon broke into the National League with the Cleveland Blues in 1880 and played until 1892 with several different teams. While his playing career was, for the most part, unexceptional he began what would be an illustrious career as manager when he took the helm of the Pittsburgh Pirates in 1889.

Hanlon moved to the Baltimore Orioles in 1892 where, despite some growing pains, he would experience his greatest success. Baltimore won the National League title from 1894 to 1896 by playing Inside Baseball, using innovative strategies including the hit-and-run. After two more successful, but not championship-calibre, seasons with Baltimore, Hanlon moved to Brooklyn to helm the Superbas in 1899. After winning the National League pennant again in 1899 and 1900, Hanlon's teams faltered. In 1905, his final season with the Superbas, his team failed to win even a third of its games. The following season, Hanlon moved to the helm of the Cincinnati Reds. He retired from managing after the 1907 season, having finished in 6th place in both of his seasons in Cincinnati.

Hanlon finished his managerial career with a 1313-1164 record. His 1313 wins ranks 26th all-time among managers. Remarkably, he led teams to seven consecutive .600-plus winning percentages from 1894 to 1900.

Hanlon was inducted into the Baseball Hall of Fame in 1996.

Ned Hanlon is interred in the New Cathedral Cemetery in Baltimore, Maryland.