In a possible preview of an Eastern Conference playoff matchup, Vanek and Jason Pominville scored goals slightly more than a minute apart in the third period to put the Sabres up by three goals in only their fourth victory in Pittsburgh in 10 seasons. They had been 3-12-5-1 there since the 1996-97 season.
The Sabres made certain their final three games of the season, all against non-playoff teams, will effectively mean nothing as Dmitri Kalinin and Derek Roy also scored in Buffalo's 51st victory of the season. The Sabres are assured of opening the playoffs next week as the top-seeded team in the Eastern Conference.
Buffalo last won a conference title, the Prince of Wales in the 1979-80 season, and hadn't won its division in 10 years.
The Penguins still can finish as high as second in the conference by winning their final two games, at Ottawa on Thursday and at home against the New York Rangers on Saturday night, but only their second regulation loss at home since Dec. 27 badly hurt their chances. They began the night in fifth place in the Eastern Conference, one point behind Atlantic Division-leading New Jersey and Ottawa, but failed to get at least a point at home for the first time in nine games.
The Sabres, competing with the Detroit Red Wings for the Presidents' Trophy as the regular season winds down, gave the youthful Penguins a lesson in playoff-type hockey. They held NHL scoring leader Sidney Crosby without a point - he had nine in his previous four games - and seemed to take advantage of any mistake the Penguins made.
After Kalinin and Pittsburgh's Mark Recchi scored in the first period, Recchi's 23rd goal but his first in 21 games, Roy's 18th goal of the season early in the second proved to be the biggest of the game. Penguins goalie Marc-Andre Fleury, who was 15-1-2 in his past 18 home games, stuck out his right pad to stop Drew Stafford's shot but Roy skated hard to the lower right circle and put the rebound past Fleury before the goalie could react.
Early in the third, the Sabres had just killed off a Daniel Briere delay of game penalty when Vanek also scored on a rebound, sweeping the puck around Fleury after the goalie stopped Drew Stafford's shot as he skated down the slot. Vanek is the first Sabres player to score 40 goals in a season since Miroslav Satan also had 40 in 1998-99, when Buffalo lost to Dallas in the Stanley Cup finals.
Pominville made it 4-1 only 66 seconds later after Jochen Hecht put a long pass on his stick in the right circle following a Pittsburgh turnover in the neutral zone.
Sabres goalie Ryan Miller made 22 saves to win for the 38th time this season, matching Don Edwards' team record set in 1977-78.
Notes: Penguins D Ryan Whitney (groin) missed a game for the first time this season. ... The Sabres' Maxim Afinogenov, out since Feb. 15 with an injured wrist, has resumed practising but remained sidelined. ... The teams split the four-game season series. ... Pittsburgh had won its past six at home.