JaQuon Parker had 12 points for the Bearcats.
Cincinnati has lost three straight and five of its last six games.
"You have to play great to win here," Cincinnati coach Mick Cronin said. "We played bad."
Notre Dame used a 13-2 run over an 8 1/2-minute first-half span to open a 19-6 lead.
Cincinnati struggled with just 3-for-15 shooting (20 percent) in the same stretch, including several misses in the paint. The Bearcats had just one field goal in a span of more than 10 minutes.
That pattern was repeated throughout the game.
"I feel like they didn't score sometimes for three- or four-minute stretches because we would get three or four stops in a row and one or two threes to go on a 10-0 run," Grant said. "Getting defensive stops was what did it."
The Irish went on to a 29-15 halftime lead as Pat Connaughton hit a baseline 3-pointer with 2.8 seconds showing. Connaughton, Cooley and Knight each had six first-half points.
The Bearcats missed their first four shots and had a turnover to open the second half. Notre Dame's Atkins, meanwhile, hit a short jumper and followed with a baseline 3-pointer to open a game-high 19-point lead at 34-15.
A different Cincinnati team then briefly emerged.