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 left.
Jerian Grant, who fouled out with 1:57 left in the first overtime, led the Irish with 19 points.
Chane Behanan had 30 points and 15 rebounds for Louisville.