Matt Howard scored 17 points and added 12 rebounds to lift Butler past Siena 70-57 on Tuesday.
Shawn Vanzant added 12 points for the Bulldogs (3-1) in a rematch of last year's Bracketbuster matchup, a similar 70-53 victory for Butler, the eventual national runner-up.
Ryan Rossiter had 26 points and 15 rebounds for the Saints (1-3, 0-0 MAAC), who lost at home for the second straight time after winning 38 consecutive home games.
Siena, which cut the lead to 62-55 with 5:28 remaining, was unable to stop the ensuing 7-0 run by Butler that clinched the win, including a strong finish by Howard at the 4-minute mark.
Thanks to 38 points off the bench, the Bulldogs survived the loss of starting guard Ronald Nored, who left the game dazed and bloodied after a collision in the game's opening minutes and did not return.
''Right when he hit, you knew he was probably out for the rest of the game,'' Butler coach Brad Stevens said. ''Our bench stepped up and did a good job of covering his absence.''
Howard had a pair of 3-pointers and a key three-point play that gave Butler a 10-point lead with 5:53 remaining.
''When things weren't going well in the second half, guys got together and said, 'We're going to get this done,''' Howard said.
The Saints fell at home in back-to-back games for the first time since January 2007.
The Saints made it a 44-41 game early in the second half on Clarence Jackson's three-point play, but Butler responded with an 8-0 run over the next three minutes to go up by double digits.
''This team is a work-in-progress. We have to get these guys confident,'' Siena coach Mitch Buonaguro said. ''When you get down nine or 10 with Butler, it's tough to come back.''
Butler erased an early 8-point deficit and headed into halftime up 37-29.