Ramon Galloway's layup with three seconds remaining proved to be the difference maker as La Salle took down No. 9 Butler, 54-53, Wednesday at Tom Gola Arena.
Tyreek Duren scored 16 points and dished out six assists and Sam Mills netted 11 points and snagged five rebounds for the Explorers (13-5, 3-2 A-10), who snapped Butler's 13-game winning streak and bounced back from a loss at Xavier on Saturday.
It was La Salle's first victory over a top-10 team since 1980.
Andrew Smith scored 16 points and grabbed eight rebounds for the Bulldogs (16-3, 3-1), who fell for the first time since Nov. 21 and dropped their first conference game of the season. Kellen Dunham added 15 points and nailed 3-of-4 attempts from 3-point range.
Back-to-back buckets by Smith gave Butler a 51-50 lead with 51 seconds remaining, but Mills answered with his own jumper that put LaSalle back up by one.
Smith's lay-in with eight seconds left looked to be the Bulldogs' prayer before Galloway, who finished with just six points on 3-of-10 shooting, drove the length of the court to nail the game-winner.
"It's the greatest feeling ever," Galloway said. "It's one of the greatest wins ever in my life. I know it is for my teammates too."
Butler, who came into the game after a dramatic buzzer-beating victory of its own in Saturday's win over then-No. 8 Gonzaga, played its third straight contest without leading scorer and senior guard Rotnei Clarke, who's been out with a sprained neck - and it showed.
The visitors led 28-23 at halftime, with Roosevelt Jones and Dunham pacing the Bulldogs by accounting for 19 of the team's points, although the Explorers were still in the game despite shooting 32.3 percent from the floor and going 2-of-9 from 3-point range.
Things looked the same for Butler into the second half, as two Jones jumpers and a pair of Dunham 3-pointers were responsible for 10 of the Bulldogs' first 12 second-half points. Butler still held onto to its edge, up 40-35 with 12:40 remaining.
La Salle had other plans, though, as Duren's layup with just under 10 minutes left gave the home team a 41-40 lead - just La Salle's second of the contest. Tyrone Garland's trey a couple of possessions later capped off a 11-2 run, giving La Salle a 46-42 lead before Butler's Smith netted three straight points to cut the edge to one point.
Mills had a chance to close things out with 14 seconds left, but he missed the front end of a 1-and-1, giving Butler the ball back down by one and leading to what looked like another thrilling win after Smith's jumper with eight ticks left.
"La Salle did a great job and certainly earned the win," Butler coach Brad Stevens said. "Both teams played hard. We were sloppy, obviously, but that was due to La Salle and not so much due to anything we were trying to do. I just thought they did a very good job."
Butler opened the game on a 9-4 run and later increased the lead to 25-15 on Jones' basket and free throw with under four minutes left before the break.
La Salle tightened things up, however, and held the Bulldogs to just three points over the last three-plus minutes of the half. Back-to-back threes by Garland and Duren then brought the home team's deficit to four points just before the break.
Clarke, who is averaging 16.3 points, was hurt when he crashed head-first into a padded basket support at Dayton on Jan. 12 ... The new conference foes had met just eight previous times previously, with Butler winning six of those matchups. The last took place in 1999 ... La Salle shot 41.1 percent from the floor, compared to 48.9 from Butler ... Garland chipped in nine points in the win ... La Salle's last win versus an AP top-25 team came in March of 2001, while its last top-10 victory came against No.8 Notre Dame in 1980.