The Golden Eagles (16-4, 5-0) also had their largest offensive output since joining the conference and tied a school record with their 23rd consecutive home victory, a feat not accomplished since 1949-51.
Dwayne Davis added 19 points, Rashard McGill 13 and Daveon Boardingham 12 for Southern Miss, which has now won eight straight and has averaged a 23.4-point margin of victory in its C-USA games.
Marshall (9-10, 2-2) got 16 points from Elijah Pittman as it fell to 0-6 on the road this year. DeAndre Kane, who entered tops in C-USA and fifth nationally with 7.6 assists per game, had just two helpers and 11 turnovers.
Southern Miss entered making a conference best 38.4 percent of its 3-pointers and drained 11 of 20 Wednesday.