Sharp tallied goals four and five on the season for the Blackhawks, who beat the Sabres in both their meetings this season. Marian Hossa extended his point streak to six games to start the season with a goal, while Dave Bolland also scored in the win.
Patrick Kane and Brent Seabrook each assisted twice, while Marty Turco made 38 saves in the victory.
Cody McCormick, Drew Stafford and Paul Gaustad all scored once for the Sabres, who have lost five straight (0-4-1) since a season-opening win in Ottawa. Patrick Lalime allowed all four goals on 21 shots in defeat.