Andy Hilbert and defenseman Mark Streit had a goal and assist each, and Jon Sim and Bill Guerin also scored for the surging Islanders (8-10-2), who won for the fourth time in five games.
Rookie Mark Mancari netted his first NHL goal, and Derek Roy also scored for Buffalo (9-8-3), which hadn't lost five in a row in regulation since March 2006.
Buffalo backup Patrick Lalime, giving Ryan Miller a rest, made 22 saves to fall to 1-3-1. His lone win this season came in a 7-1 victory at the Islanders on Oct. 13.
After starting 8-2-2, the Sabres are in the midst of a 1-6-1 slide.
It was the second straight game that Buffalo was stymied by a goalie on top of his game. Martin Biron made 40 saves Friday night in Philadelphia's 3-0 win over the Sabres.
MacDonald turned aside 31 shots over the first two periods, including 18 in the second to keep the Islanders' one-goal lead intact. New York recorded only two shots in the period but outscored the Sabres 1-0.
Guerin capitalized four minutes into the third when he scored his seventh goal to push New York's lead to 3-1.
Roy made it 3-2 when he beat MacDonald with a slap shot from the top of the left circle with 4:34 to go, but Streit capped New York's win with an empty-net, power-play goal with 2 seconds left.
Hilbert opened the scoring 14 minutes in with his fifth goal.
Trent Hunter's shot from the slot ricocheted off Hilbert before bouncing over Lalime to make it 1-0.
Mancari tied it with 1:01 left in the opening period. After MacDonald stopped Paul Gaustad's shot from the left circle, Mancari shoveled in the rebound.
Buffalo had allowed nine consecutive goals over three games before the tally.
The Islanders regained their one-goal cushion on Sim's fifth goal at 7:41 of the second period. On the power play, Streit's slap shot from the right point went off Sim and past Lalime to give New York a 2-1 edge.
