Gabriel Landeskog had a goal and two assists to reach 500 career points for the Avalanche, who have won seven of eight. Jonas Johansson made 24 saves.
''We had a little talk before the game that we needed to step up with our speed and our skating, and I think everyone on the team did their best today,'' said Johansson, who made 28 saves in a 2-0 win against the Ducks on Friday.
Colorado went 6-1-1 in the season series against Anaheim.
Jamie Drysdale scored and John Gibson made 33 saves for the Ducks, who are 1-4-1 in their past six.
''We gave them a few too many good scoring chances from the slot,'' Ducks defenseman Kevin Shattenkirk said. ''We played hard, it's not for lack of trying. They are a team that's going to generate scoring chances on a nightly basis with the skill and talent that they have.''
The Ducks cut it to 2-1 at 12:37 of the third period when Drysdale scored on a long shot through traffic, but Ryan Graves' shot deflected off two Anaheim players to give Colorado a two-goal lead again at 14:13.
MacKinnon made it 4-1 at 16:54. He has six goals and nine assists during his streak, the longest for the Avalanche this season.
Avalanche coach Jared Bednar said MacKinnon's latest stretch of point production is ''nothing out of the ordinary.''
''I just think he's starting to dial up his 200-foot game and he's making plays,'' Bednar added. ''Tonight, he went to the net hard, he gets rewarded at the end of the game.''
Landeskog had the secondary assist for his 500th point, becoming the second player from the 2011 draft class to reach that milestone. He has 214 goals and 286 assists in 672 games.
''He has a lot of strengths to his game, and I think consistency has improved in the time that I've been here,'' Bednar said. ''What I noticed about him is he's unselfish, team-first guy. He's going to be committed to your team game and helping sell your team game. And if you're going to talk and lead the way Gabe has to and does, then you have to be willing on a nightly basis to back it up. And that's what his play does.''
Landeskog gave Colorado a 2-0 lead at 6:35 of the second by tipping MacKinnon's shot from the high slot during a power play with a two-man advantage.
It was the Avalanche's first 5-on-3 goal this season. They entered with a league-leading 35 goals in 5-on-4 situations.
Andre Burakovsky put the Avalanche up 1-0 at 7:46 of the first with a wrist shot from the slot after stealing the puck from Cam Fowler. Burakovsky's third goal in four games came less than 30 seconds after Johansson denied Max Jones twice off a 2-on-1 rush.
After being traded to the Avalanche from San Jose on Saturday, goalie Devan Dubnyk joined his new team after having a car service drive him down the California coast and avoid any quarantine that would have come with traveling on a commercial flight.
''When I was sitting in the car, it kind of hit me a little bit that how great of an opportunity this is to have a chance to win a Stanley Cup,'' he said.
Dubnyk, who last played for the Sharks on March 27, isn't sure when he will make his first start for Colorado after backing up Johansson on Sunday. Bednar said Philipp Grubauer would start against Arizona on Monday.
While the addition of Dubnyk gives the Avalanche another goalie with playoff experience, Johansson said after playing in just his 18th NHL game it doesn't change anything for him.
''What's up to me is what I do on the ice, so I'll play if they tell me to play. I'll just do my part as best as I can, whatever that is,'' Johansson said.
If the Ducks are going to be sellers before Monday's trade deadline, there were no clues as to who might be moved from their lineup choices against Colorado. Nicolas Deslauriers, the subject of trade chatter earlier in the day, played 7:22 and got in a fight in the first period.
Avalanche: Host Arizona on Monday. ?
Ducks: At San Jose on Monday.
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