Green Wave quarterback Ryan Griffin was sacked six times and fumbled twice in his debut as a starter.
Jamie Collins scooped up one of Griffin's fumbles and returned it 15 yards for a touchdown in the second quarter and Andre Watson returned a blocked field goal 75 yards for another score.
Tory Harrison led Southern Miss (5-3, 3-1 Conference USA) with 93 yards and a touchdown on 14 carries.
The Golden Eagles held Tulane (2-5, 0-4) to 208 yards of offense.
Andre Anderson rushed for 92 yards and scored Tulane's lone touchdown in the third quarter.