Natalie Novosel led the way with 21 points 70, at Purcell Pavilion on Sunday.
The Fighting Irish (23-1, 10-0 Big East) had five scorers in double figures including 16 points and five rebounds from Natalie Achonwa. Skylar Diggins added a double-double with 11 points and 10 assists for Notre Dame, which has now won 20 straight games.
Jasmine Penny finished with 24 points and Katherine Harry added 20 points and nine rebounds for DePaul, (17-7, 5-5) which was coming off back-to-back wins after losing three in a row.
The Fighting Irish finished the first half shooting 71.9 percent including 6-of-7 from long range to take a 56-31 lead at halftime.
Notre Dame cooled off as it finished the game just under 60 percent from the field, but DePaul struggled all game, especially from long range, as they finished just 2-of-12 from beyond the arc.