Kyle Kuric hit two of his three 3-pointers in the final five minutes, finishing with 17 points, and Chris Smith scored 13 of his 15 points in the second half, leading the Cardinals to a 69-53 victory and a rare home loss for the Bulldogs.
Louisville (3-0) was the highest-ranked team to visit Hinkle Fieldhouse since No. 5 North Carolina in 1992, and fans were lined up outside in chilly temperatures and rain more than 90 minutes before tip-off.
For 30 minutes, the two-time national runner-ups reverted to old-school basketball and it kept the Bulldogs close.
But in that closing flourish, Butler's defense broke down, and Kuric and Smith repeatedly made the Bulldogs pay for the mistakes.
Kuric was 7 of 11 from the field, 3 of 6 on 3-pointers. Louisville needed Smith to play well, too, with starting guard Peyton Siva sitting out because of a sprained left ankle and point guards Russ Smith and Elisha Justice in foul trouble.
Both eventually delivered.
Butler (1-2) was led by Khyle Marshall with 20 points and Chase Stigall, who scored all 11 of his points in the first half. It was only the sixth home loss in coach Brad Stevens' four seasons with the Bulldogs.
Butler controlled most of the first half, scoring the first five points and maintaining that narrow lead until Jared Swopshire scored on a driving layup with 2.4 seconds left in the first half to give Louisville its first lead, 29-28.
Chrishawn Hopkins' buzzer-beating half-court heave would have put Butler back in the lead, but it bounced off the backboard just left of the basket.
But the Cardinals turned things around in the final 20 minutes.
Louisville opened the second half by scoring the first five points to make it 34-28.
Marshall answered with back-to-back baskets, and the Bulldogs retook a 37-36 lead when Hopkins made two free throws with 14:45 to go. They led again 41-40 when Ronald Nored made two free throws.
This time, though, the Cardinals answered with Smith's three-point play, which led to an 11-2 run and gave Louisville a 51-43 lead with 9:40 left. Kuric's 3 over the 6-foot-8 Kameron Woods made it 56-45 with 6:10 to play, the first time either team led by double digits and his next 3 made it 61-47, sealing the outcome.