Holloway grabbed the ball from Blue Demons forward Cleveland Melvin and dashed downcourt for the score.
Holloway had 16 points and 12 rebounds for the Rebels (6-1), who led by 17 points early in the second half. Brandon Young had 18 points for DePaul (4-2), and Melvin added 14 points and 10 rebounds.
The victory was the third straight for Ole Miss and second in three meetings against the Blue Demons.
The Rebels built a double-digit lead while DePaul failed to make a field goal in the final 7:04 of the first half.