Freshman Wade Korpi started on the mound for the Irish and pitched well for the first five innings, allowing zero runs on just three hits.
Korpi battled in the top of the sixth, but tired as he gave up the Frost solo shot on a full-count pitch.
Frost's homer blew the game open for USC as the Trojans picked up three runs in the sixth, four runs in the seventh, and two runs in the eighth to total their nine runs on the evening to earn the split with Notre Dame.
After back-to-back impressive offensive showings by the Irish in the two previous games, Notre Dame could muster just three runs on seven hits.
Also on the line on Wednesday was Notre Dame's 199-game scoring streak. USC threatened to break the streak as Trojan pitchers shut out Notre Dame for seven innings at the plate until the Irish could push a run across in the bottom of the eighth.
Irish head coach Paul Mainieri was again scratching his head after Wednesday's performance.
"If you could figure this sport out, please let me know about it," said Mainieri. "I've been in it my whole life, and from one night to the next, it's like two different teams.
"We played two great games in a row, and tonight, we played about as poorly as we could in every aspect. The pitching wasn't bad, Korpi did a pretty good job, but we seemed like we couldn't get a good at-bat when the game was in balance. We couldn't make a big play."
Notre Dame (30-22-1) will close out their regular season this weekend as they host West Virginia in a Big East showdown with a lot a stake.
Notre Dame is currently in third place in the Big East standings, and the Irish must remain in the top four in the conference to make the Big East Tournament. Their performance this weekend against the Mountaineers will determine if they'll extend their season to the post season.
The three-game series starts on Friday with a doubleheader that begins at 3 PM at Frank Eck Stadium.