Neil Watson had 15 points and Jerrald Brooks 12 for the Golden Eagles (7-3), who snapped a three-game losing streak.
Terry Rose led Grambling State (0-8) with 18 points. The Tigers have played all their games on the road.
Holding an 11-7 lead 3:48 into the game, the Golden Eagles scored 19 consecutive points and rolled to a 50-21 halftime advantage.
Southern Miss shot 59.6 percent from the field (34 of 57) to Grambling's 32.6 percent (15 of 46) and outscored the Tigers 18-6 from the foul line. Southern Miss outrebounded Grambling 36-23.
Southern Miss won the only other meeting between the teams, a 70-52 victory in the Super Chevy Shootout in Iowa City, Iowa, during the 1996-97 season.