The No. 8 seed Bulls (14-19) handed the No. 5 seed Cardinals (15-15) their first loss in six games and just their second in the last nine. Buffalo will advance to meet No. 4 seed Kent State in Thursday's third round.
"I'm proud of what our seniors did leading this team," Ball State coach Billy Taylor said. "It was a team that could have given in when we were in 11th place. But we fought and battled and earned a bye. We just could not get it done tonight."
Scaife knocked down a career-high seven 3-pointers Wednesday at Quicken Loans Arena as the senior guard broke Patrick Jackson's school record for career treys with 203.
Ball State held a lead at halftime but struggled to contain Buffalo forward Will Regan, who poured in 36 points on the night, including 25 after the break.
Ball State held Buffalo to 28.6 percent shooting in the first half, but the Bulls made good on 12 of 13 free throw attempts to keep things close. Then Buffalo found its stroke in the second half and shot 64 percent over the final 20 minutes.
"I thought our defense in the first half was pretty good against their spread," Taylor said. "In the second half, we just didn't make all the plays we needed to make defensively. It seemed like every time we made a mistake, they capitalized with a 3 or another basket, and it's hard to win when a team is clicking like that offensively."
Ball State led by as many as 10 points late in the first half after Scaife keyed a run by making his last four field goals of the half. The Cardinals took a 36-30 lead into the break, but Buffalo came out on fire to start the second.
Regan hit three 3-pointers in the opening minutes of the second half and Buffalo grabbed the lead at 42-39. A Jesse Berry trey and a Matt Kamieniecki free throw put the Cardinals back on top 43-42, but that was the last time the Cardinals would lead.
Buffalo went on a 15-1 run over the next five minutes to take a 57-44 lead midway through the second half. The Cardinals pulled within eight multiple times down the stretch but no closer.
Regan scored his 36 points on 11-of-17 shooting and 9-of-9 from the free throw line. Javon McCrea joined him in double figures for Buffalo, scoring 18 points to go along with a game-high 11 rebounds.