The win marks the 14th straight time the Racers (11-5, 4-2) have beaten Jacksonville State since joining the OVC in 2004.
Murray State trailed throughout the opening half before a jumper from Shawn Jackson with 4 seconds left before halftime tied the score 32-32.
A layup from Jeffery McClain with 16:36 left to play gave the Racers their first lead, 41-40. McClain finished with 13 points.
Murray State stretched its lead to as many as 12, thanks to a 13-of-24 second-half shooting effort (54.2 percent).
B.J. Miller scored 20 points and Nick Murphy added 14 for the Gamecocks (2-15, 0-6), who have lost 11 consecutive games — their longest losing streak since a 14-game slide during the 2004-05 season.