Nathan MacKinnon scored twice, and Tyson Jost, Colin Wilson and Carl Soderberg had goals in a 5:35 span of the first frame to give Colorado its first road win of the season. Alex Kerfoot also scored, Mikko Rantanen had three assists, and Semyon Varlamov stopped 30 shots for the Avalanche.
Nathan Beaulieu scored and Carter Hutton had 24 saves for the Sabres, who wound up with two wins on their four-game, season-opening homestand that ended Thursday.
The Avalanche managed a split on their short two-game road trip thanks to superior special teams against the Sabres. Colorado was 2-for-4 on the power play and killed all seven penalties it drew.
Jost got the Avalanche started with a goal at 10:55 of the first period. With Jack McCabe in the box for hooking, Colorado moved the puck around the zone to Tyson Barrie at the point, who sent it to the net. Jost tipped it past Hutton for his first goal of the season.
Barrie had two assists on the night.
Colorado went back on the power play a few minutes later, and Wilson made it 2-0 with his third goal of the season.
Soderberg made it 3-0 at 16:30 when he put a high shot over the goaltender's left shoulder. It was his third goal of the season.
Buffalo thought it scored on the power play in the final minute of the first period, but the goal was waved off for goaltender interference.
The Sabres finally got on the board late in the second period. Beaulieu took a shot from the point that went between Varlamov's pads and trickled through at 17:05. The celebration didn't last long. Just 28 seconds after Beaulieu's first goal of the season, MacKinnon scored to make it 4-1.
MacKinnon has scored at least one goal in each of Colorado's first four games.
Kerfoot and MacKinnon scored on breakaways late in the third period.
(With inputs from agencies.)