The Cardinals held Southern Mississippi to just 13 points in the first half. The Golden Eagles shot a mere 29 percent from the field and turned the ball over 21 times.
Jones scored his 18 points in 23 minutes with Russ Smith and Montrezl Harrell both chipping in 11.
Louisville is 6-1 for the campaign and handed Southern Mississippi its first loss in seven games.
The Golden Eagles did not have a player reach double figures. Michael Craig led the way with nine points.