MacKinnon has scored in each of Colorado's first four games, which is tied for the second longest streak to begin a season in Avalanche/Quebec Nordiques history (Mats Sundin, five in 1992-93).
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"I think I can play better than I am," MacKinnon said. "I'm just putting them in right now, but I think, overall, it hasn't been the easiest year so far. Our line's gotten better, like we played last season, but it's nice to score some goals."
Tyson Jost, Colin Wilson, Carl Soderberg and Alex Kerfoot scored, Mikko Rantanen had three assists and Semyon Varlamov made 30 saves for Colorado (3-1-0).
"I know the guys were excited to play tonight and bounce back and rebound from the other night (5-2 loss to Columbus Blue Jackets on Tuesday), and I thought we cured that," Avalanche coach Jared Bednar said. "Great first period. We were skating, checking hard, arriving in D-zone coverage and finishing checks off."
Nathan Beaulieu scored, and Carter Hutton made 24 saves for the Sabres (2-2-0). Rasmus Dahlin, who was the No. 1 pick in the 2018 NHL Draft, got an assist for his first NHL point.
Jost gave the Avalanche a 1-0 lead on the power play at 10:55 of the first period when he redirected Tyson Barrie's shot from the point. Wilson made it 2-0 at 13:20 after he got a rebound in the slot and beat a screened Hutton on the power play.