Paul Statsny also scored and Jean-Sebastien Giguere made 28 saves for the Avalanche, who bounced back from their first loss of the season against Detroit on Thursday.
Cody Hodgson and Marcus Foligno scored for Buffalo, which got more than one goal for only the third time in 10 games this season. The Sabres remained winless in six home games after finishing up a stretch of four games in six days.
The Avalanche scored four times in the first 32 minutes and that was more than enough against a Sabres team that has not scored that more than three regulation goals in a game this season.
Foligno gave the Sabres some hope 1:05 into the third period, getting the rebound of Henrik Tallinder's shot and lifting the puck over a fallen Giguere to cut Colorado's lead to 4-2.
The Sabres outshot the Avalanche 16-4 in the third period, but could not find the back of the net. A flurry of three close-range shots with just under six minutes left in the game were all blocked by Avalanche defenders.
Statsny scored his first goal of the season to give the Avalanche a 4-1 lead 8:34 into the second period.
Hodgson put Buffalo on the board 5:31 into the second, streaking up the right side and striking a slap shot from the top of the circle past Giguere.
Duchene took a pass from O'Reilly in front of the net and converted a power play 56 seconds into the second period to make it 3-0.
Landeskog gave Colorado a 2-0 lead with 8:03 left in the first period, weaving up centre ice on a delayed penalty and beating Ryan Miller with a wraparound.
The Avalanche scored before the Sabres could get a shot on goal when Duchene came from behind the net and fed O'Reilly on the left side of the crease at 8:44 of the first period.
The Sabres' first shot on goal came with 5:50 left in the first period and drew a loud ovation from the crowd. Colorado outshot Buffalo 14-3 in the first period. It was the second time this season the Sabres have managed just three shots in a period.
NOTES: Buffalo added rookie D Nikita Zadorov to the active roster Saturday and sent fellow first-round pick D Rasmus Ristolainen to AHL Rochester. Zadorov can play up to nine games with the Sabres before activating his entry-level contract. . Colorado rookie C Nathan MacKinnon, the first overall pick in this year's draft, will face fellow Nova Scotia native Sidney Crosby for the first time Monday when the Avalanche play in Pittsburgh. . Miller made 22 saves for Buffalo.