It was the Mountain Hawks fifth win in their last six games over the Crusaders, and their first 50-plus point scoring game in regulation since 2005.
Dominick Bragalone ran for 116 yards and a touchdown for Lehigh (5-4, 3-1 Patriot League), and Gatlin Casey added 87 yards receiving including a game long 44-yard touchdown catch.
Lehigh led 41-10 at halftime on the strength of a 27 point outburst in the second quarter. A Nana Amankwah-Ayeh 1-yard touchdown run for the Mountain Hawks made it 51-24 late into the fourth.
Holy Cross (4-5, 1-3) added two late scores; including a 38-yard touchdown run by Gabe Guild to finally cut the deficit below 20 points.
Peter Pujals threw for 311 yards and three touchdowns for the Crusaders.