Russ Smith had a chance to tie it, but his 3-point attempt missed before Notre Dame students flooded the court to celebrate. It marked the sixth time in the last eight meetings that a game between the Fighting Irish (19-5, 7-6 Big East) and the Cardinals (19-5, 7-4) went into overtime.
Both teams missed crucial free throws in the final minute. Atkins missed two with 37 seconds left and Montrezi Harrell did the same for Louisville with 24 seconds to go.
The lead changed hands 26 times and the score was tied 16 times.
Jerian Grant, who fouled out with 1:57 left in the first overtime, led the Irish with 19 points. Garrick Sherman, getting more minutes after Jack Cooley and Tom Knight fouled out, added 17 points on 7-of-10 shooting as the Notre Dame bench outscored Louisville's 39-31.
Pat Connaughton had 16 points and 14 rebounds, Atkins added 14 points, and Cooley, who fouled out with 6:54 left in regulation, finished with 11 points and 11 rebounds.
Chane Behanan led Louisville with 30 points and 15 rebounds. Luke Hancock added 22 points, Smith had 21 points and 10 rebounds, and Gorgui Dieng had 17 points and 13 rebounds.
Both teams needed big shots to force the extra periods. In the fourth overtime, Atkins and Zach Auguste missed shots for the Irish, but Garrick Sherman tipped in the rebound to tie the score at 93 with 5 seconds left. Russ Smith had a last-second shot for the Cardinals but missed.
In the third overtime, Behanan scored inside with 16 seconds to go to tie it at 83. With 16 seconds left in the second overtime, Cameron Biedscheid hit a 3-pointer to force another period.
Both teams missed chances to win in the first overtime. Behanan blocked a shot inside by Notre Dame's Eric Atkins with 15 seconds left before Smith missed from 3-point range in the closing seconds for the Cardinals.
It didn't look as if the Cardinals were going to need overtime when Behanan made a free throw with 51 seconds left in regulation to make it 56-48. But Grant led the Irish on a 12-4 comeback, hitting three straight 3-pointers and then tying it on a three-point play with 16 seconds left. The Cardinals had a chance to win, but they never got a shot off as Siva lost control of the ball under the basket in the closing seconds.