The Midshipmen's six-run fourth inning sunk the Nittany Lions' hopes of a Sunday victory.
Penn State is still expected to get a home game in the first round of the NCAA tournament.
Despite a positive start, Penn State could not handle Northwestern and fell short of the championship.
The Nittany Lions dropped a Saturday doubleheader after winning game one.
The Nittany Lions have a 6-2 all-time record against the Bulls, but haven't faced Buffalo since December 2004.
Travis Luensmann had a season-high nine strikeouts en route to a dominant win on the road.