P.J. Hairston scored 20 points and snagged eight rebounds for North Carolina (9-3) and Reggie Bullock hit five 3-pointers and 17 points for the game.
North Carolina remained undefeated at home this season.
Jeremie Mitchell led McNeese State (6-4) with 13 points and Craig McFerrin added 10 points.
The loss ended the Cowboys' five-game win streak.
The Tar Heels shot 47.3 percent from the field and out-rebounded the visitors 52-36. Carolina went on a 17-0 run early in the game and led 54-23 at halftime.
Coach Roy Williams emptied its bench in the second half for mop-up duty.