Colby's lacrosse program has a tradition of success dating back to 1964. During the 2002 campaign the program reached new heights with a first-ever NESCAC championship game appearance (Colby lost to Middlebury 14-9) and a ranking of 17 in the final national poll. The Mules experienced much success in the '90s, compiling a 95-43 record. During that span Colby had seven ECAC appearances and one NESCAC championship game berth. Regionally, Colby has been consistently ranked in the top 10 of the New England Coaches poll and is one of the area's more dominant teams.

Colby's lacrosse program has produced five All-Americans: midfielder Kevin Plummer ’89 (Denver, Colo.), attacker Matt Williams ’99 (Cape Elizabeth, Maine), defender Gabe Duncan-Roitman ’02 (Denver, Colo.), goalie John Shea ’02 (Mountain Lakes, N.J.), and midfielder Craig Bunker '11 (Topsfield, Mass.).