DeQavius Walker returned the opening kickoff 84 yards and Murray State (3-5) built a 27-10 lead after one quarter, 41-29 at halftime and then scored 31 points in the third.
Murray State outgained Kentucky Wesleyan 408 to 14 on the ground. Pokey Harris led the way with 10 carries for 176 yards and a score. Nick Taylor and CJ Bennett both had a rushing TD and Marcus Holliday had two scores on four carries.
Dalton Oliver completed 29 of 47 passes for Kentucky Wesleyan (4-4) and had two touchdown passes. Xavier Mitchell caught nine balls for 102 yards and a score.
Murray State set a school single-game scoring record, eclipsing its 83-point mark in 2013 against Campbellsville.