Wilkes hit a go-ahead 3-pointer with 0.1 seconds remaining, lifting UCLA to a 65-62 victory over Notre Dame on Saturday night after the Bruins blew a 14-point lead.
Wilkes ran backward, staggered and collapsed in agony as his teammates erupted in celebration near the basket.
"I went to celebrate with him and he was on the ground like, Come on, get off me, my leg," Jaylen Hands said.
Wilkes then raised his head and pounded his right fist on the floor.
"That was a great shot," he said about just his second basket in the final 20 minutes.
Jalen Hill blocked a layup by Prentiss Hubb, Prince Ali grabbed the defensive rebound and fed Wilkes near the right top of the key for the game-winner in the first meeting between the longtime rivals since 2009.
"That's why we wanted the rivalry back, to have games like that," UCLA coach Steve Alford said. "What set up that shot was we got huge stops inside that minute."
Wilkes finished with 14 points. Hands and Ali added 12 points each for the Bruins (7-2).
"For a young, inexperienced group to have a big lead and lose it and be down five inside three minutes and find a way to win, that's growth and that's what we wanted to see," Alford said.
Rex Pflueger led the Fighting Irish with 14 points, making all four of his 3-pointers, in his homecoming game. D.J. Harvey added 13 points and John Mooney had 12 points and 11 rebounds.
"This one definitely stings, especially after losing to Oklahoma in a close game," Mooney said. "Then, coming in here, playing hard, losing at the end, it hurts."
UCLA led by 14 early in the second half, but the Irish (6-3) regained the lead on a pair of free throws by Hubb with 5:52 remaining as part of a 12-0 run.
Pflueger's 3-pointer kept the Irish ahead 62-57 before Ali dunked. He later got fouled on a 3-point attempt and made all three free throws to tie it at 62-all after missing 2 of 3 free throws with 5 1/2 minutes to go.
UCLA couldn't buy a basket in the paint or at the rim during a scoreless stretch that lasted four-plus minutes before Ali's dunk. But the Bruins' defense held up and the Irish didn't score over the final 3:39.
"Love that we gave ourselves a chance to win," Irish coach Mike Brey said. "Got to give credit to UCLA. They made some big plays at key times."
It was the 49th meeting in the series that began in 1952. UCLA owns a 29-20 advantage. It was just the eighth time in series history that neither team was ranked in the Top 25.
Both teams struggled offensively in the first half when UCLA closed with 11 straight points by five different players to lead 31-20.
The Irish shot 23 percent and scored their fewest points in a half this season. Thanks to their late scoring spurt, the Bruins raised their shooting to 32 percent but still had their second-fewest points in a half.
Notre Dame: It was the first true road game of season for the Irish after playing their first seven at home -- with six wins -- and then losing to Oklahoma at Madison Square Garden on Tuesday. "I told them, I think we got better this week," Brey said "We don't have a win to show for it but I think we got better."
UCLA: The Bruins secured an important win over an ACC team that could bolster their resume in March. Awaiting them on the road in the next two weeks are Cincinnati and No. 19 Ohio State.
The motivation for Notre Dame to resume the home-and-home series was to bring team captain Pflueger back home in his final season. The senior guard helped Mater Dei High in Santa Ana to the school's first-ever undefeated season of 35-0 in 2013-14.
"Usually when you bring a guy home he's a mess. Rex Pflueger was a warrior the whole night," Brey said. "I know he's so disappointed because he wanted his team to get a win here, but Rex Pflueger's a big-time winner. To come in with 200 friends and family members and play his backside off, it was fabulous."
The resumption of the rivalry brought out some famous UCLA stars from the past, including Jamaal Wilkes, Marques Johnson, Sidney Wickes and Jelani McCoy. Bill Walton, the Bruins center when Notre Dame snapped UCLA's 88-game winning streak in South Bend in January 1974, worked the game as a TV analyst. He held up a sign during a second-half timeout that read "Digger is a wimp," a reference to former Irish coach Digger Phelps. John Wooden's daughter, Nan, sat behind the Bruins' bench.
Notre Dame: Plays Purdue in the Crossroads Classic at Indianapolis on Dec. 15.
UCLA: Hosts Belmont on Dec. 15 in the last of four straight home games.
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Brown blows dunk attempt from Hands' lob
Jaylen Hands tries to get fancy and sets up Moses Brown with a lob pass, but Brown completely blows the dunk attempt.