The sixth-seeded Bulldogs (26-8) face the 11th-seeded Bison (28-5) in Lexington, Ky., on Thursday in the East region.
Butler is coming off a loss in the Atlantic 10 tournament semifinals to Saint Louis. Coach Brad Stevens said his team got worn down after playing three games in three days against the physical Billikens.
The Bulldogs are a mid-major power, two years removed from back-to-back appearances in the NCAA title game.
But tested Bucknell has its own history of NCAA upsets, including a defeat of powerhouse Kansas in the 2005 tournament. This year's squad is led by standout senior Mike Muscala, a jump-shooting center who can take over games in the post.