Notre Dame came back from six runs down to take a one-run lead in the top of the ninth, but Alec Lowry's two-run double in the bottom of the ninth gave host Louisville a 7-6 victory in the opener of a three-game Big East series on Friday night.
The Irish fall to 23-16 overall and 8-8 in the Big East while the Cardinals jump to 29-11 overall and 12-4 in the league.
The Cardinals scored four in the bottom of the first and added a pair in the bottom of the second to grab an early 6-0 lead. But, after surrendering seven hits in the first two innings, Notre Dame starter Cole Johnson settled down and allowed just three over his final four frames.
The Irish offense finally got going in the sixth with a rally that was started by Jeremy Barnes' leadoff homer. Mick Doyle and Greg Sherry laced RBI singles before A.J. Pollock blasted a three-run homer to tie the game 6-6.
Notre Dame took the lead on David Casey's one-out, pinch-hit homer in the top of the ninth.
Irish closer Steven Mazur had entered the game in the bottom of the eighth and was able to get out of a two-on, one-out jam with a line-drive double play.
In the ninth, Mazur allowed a leadoff single to Louisville's Andrew Clark before getting a pop out. The Cardinals' Phil Wunderlich followed with a double before the Irish intentionally walked Ryan Wright to set up the possibility of a game-ending double play.
Lowry pinch hit for Jeff Arnold and instead of bouncing into a twin killing, Arnold bounced the first pitch from Mazur into the right field bullpen for a ground-rule double to give Louisville the victory.
Barnes and Doyle led the Irish offense with a pair of hits apiece.
Game two of the series is scheduled for 4 p.m. on Saturday before the series finale on Sunday.