Vasturia scored a career-high 24 points and hit a late bucket again to lead No. 23 Notre Dame to a 77-70 ACC upset of the Cardinals.
Vasturia's fallaway one-hander in the lane with 19 seconds to play put the Irish up 73-68 and they hit four straight free throws from there to seal the win.
"We said in the huddle with about two minutes left that we like being in this situation," Vasturia said. "They had a big guy on me and I figured I could get into the lane and try to get something up."
Now a senior, Vasutria's late heroics come as little surprise to his coach, Mike Brey.
"He's so good at sensing when it's time," Brey said. "He finished great at Pittsburgh and that probably jump-started him a little bit. He was feeling good."
Matt Farrell tied his career high with 22 points for the Irish (13-2, 2-0 ACC), who have now won four straight overall and six in a row at home against Louisville. The Cardinals (12-3, 0-2) have not won in Purcell Pavilion since 1994.
Bonzie Colson recorded his ninth double-double of the season for Notre Dame, finishing with 18 points and 14 rebounds, despite going against defenders several inches taller than him.
"Bonzie against a frontline like that, he just takes them on," Brey said.
Donovan Mitchell scored 20 points to lead Louisville. The ACC's leader in steals, Mitchell added five steals to go with five assists and four rebounds.
"Donovan played well," Louisville coach Rick Pintino said. "He's trying to play like a star. He's not the problem right now. It's just little defensive things that are keeping us from getting over the hump."
Quentin Snider added 12 points for the Cardinals.
While the Irish missed six straight field goals, Louisville scored four consecutive points to tie the game, 68-68 with two minutes to play. Notre Dame only got the one field goal from there, but did the rest of their work from the line.
"We played well enough to win tonight but if you have a free-throw shooting contest with Notre Dame, you're going to lose," Pitino said.
The best free throw shooting team in the country, the Irish shot 22 of 25, including 15 of 16 in the second half.
"We said drive the heck out of it," Brey said. "Because we drove, we got to the foul line and the foul line was a great weapon for us."
Farrell's 3-pointer with 16:16 left capped a 9-2 Notre Dame run and pushed the Irish lead to nine, but Louisville answered with seven straight, a spurt that included two offensive putbacks by Ray Spalding.
Louisville came in as the top rated team in adjusted defensive efficiency according to Ken Pomeroy, but the Irish had 42 points by halftime and took a five-point lead into the break.
The Cardinals also came in sixth in the nation in blocked shots at 6.6 per game, and finished with seven, six of them from center Anas Mahmoud.
As Farrell drained the second of two free throws with 1:05 left to give the Irish a three-point lead, Brey called out, "Now get a stop!"
The Irish did just that, with V.J. Beachem getting a steal, which eventually led to Vasturia's bucket. That was one of a pair of Louisville turnovers in the final 1:20.
"We had two crucial turnovers that didn't give us a chance to win the game," Pitino said.
Louisville: The Cardinals' spot in the top 10 looks to be in jeopardy after their second loss to a ranked team in eight days.
Notre Dame: The Irish finally cracked the code of taking down a ranked team after losses to No. 1 Villanova and No. 15 Purdue. Next they'll try to keep their momentum going against a Clemson team still stinging from a tough loss to North Carolina.
Louisville: Despite recent big wins over Kentucky and Indiana, the Cardinals are now looking at an 0-2 hole in the ACC standings. After one more road contest at Georgia Tech, they'll try to get right at home with three straight at the Yum Center.
Notre Dame: Irish coach Mike Brey has talked about the importance of one-game win streaks in the ACC, but at 2-0 now, they'd like to see how far this streak can go. Following a home game with Clemson, three straight on the road will be a tough test.
Louisville: The Cardinals travel to Atlanta to face Georgia Tech on Saturday.
Notre Dame: The Irish host Clemson on Saturday.