The victory by the Cardinals (14-4, 4-1 Atlantic Coast Conference) spoiled the return of Matt Farrell for the Irish (13-6, 3-3) in front of a sellout crowd.
Farrell, who missed the previous three games with an ankle sprain, scored 23 points and dealt eight assists. He went just 2 of 14 from the field (both 3-pointers) after halftime.
Martinas Geben, highlighted by some dominant play in the extra sessions, finished with career highs of 22 points and 17 rebounds for the Irish. He was 10 of 13 from the field.
Farrell missed a 3-pointer from the left corner as regulation expired and was off on a possible game-winning shot with 2.2 seconds left in the first OT.
Louisville, a game behind 5-0 Virginia in the ACC, won at Notre Dame for the first time since February 1994, ending a streak of six straight losses at Purcell Pavilion.