Blackhawks forward Patrick Kane extended his point streak to 14 games, the longest in the NHL this season, with a second-period goal. He has 23 points (10 goals, 13 assists) in that span.
J.T. Compher had a goal and two assists, and Pavel Francouz made 34 saves for the Avalanche (15-8-2), who have won two games in a row after losing two straight.
[WATCH: All Avalanche vs. Blackhawks highlights]
MacKinnon has 17 points (seven goals, 10 assists) in the past eight games, all without injured linemates Mikko Rantanen and Gabriel Landeskog. Rantanen is expected to play Saturday in Colorado in the second game of the home-and-home against Chicago after missing 16 games with a lower-body injury he sustained Oct. 21 against the St. Louis Blues.
"When we get some injuries like this, [MacKinnon's] really put the team on his back," Avalanche coach Jared Bednar said. "He's been consistently hard and heavy on pucks, he's using his speed, he's finding a way to contribute every night, he's making his linemates better while doing it. That's what you need from your stars, and he's certainly been the guy who's been carrying the bulk of the load with some of the guys we've had injured."
Video: COL@CHI: Makar wrists home power-play goal
Zack Smith scored, and Corey Crawford made 18 saves for the Blackhawks (10-10-5), who are 1-3-1 in their past five games.
"It was a big divisional game, and we didn't give ourselves a sniff the entire night," Chicago captain Jonathan Toews said. "I don't know if we had as many good chances as they did. I give them credit, they're a good team. We didn't start well enough, gave up a lot a little too early."
MacKinnon gave the Avalanche a 1-0 lead 59 seconds into the game. Compher shot from the top of the left face-off circle, and MacKinnon tipped it in.
The Avalanche made it 2-0 at 3:17. Joonas Donskoi passed from the right corner to MacKinnon, whose point shot was redirected off Crawford by Matt Nieto. Ryan Graves put in the rebound from the bottom of the left circle.
The Blackhawks closed to 2-1 on Smith's goal at 9:14. Ryan Carpenter won a puck battle with Avalanche defenseman Ian Cole behind the net and passed to Smith in the slot.
Colorado increased the lead to 3-1 on Cale Makar's power-play goal at 12:20. MacKinnon passed to Makar at the top of the circles for a screened shot by Crawford's glove.
"I think nowadays, a lot of guys pull in and shoot," Makar said. "It's just more deceptive. You want to change it up, but sometimes it's just like that and I had the defender in front of me, so I decided to pull that one and just shoot it.
"We had some really good offensive opportunities, and it was just a night when we were able to capitalize on more of them than maybe we have been lately."
Video: COL@CHI: Kane extends point streak to 14 games
Valeri Nichushkin made it 4-1 at 9:45 of the second period with a backhand on a breakaway. It was his second goal in three games after he went 91 games without one.
Compher made it 5-1 at 11:26 with a short-side shot from the right circle off a pass from MacKinnon on a 3-on-1.
Chicago closed to 5-2 at 19:56 on Kane's backhand after he moved through the slot.
"They were just cleaner in the beginning and they found a way to get pucks to the net, and when you do that, you give it an opportunity to go in," Blackhawks coach Jeremy Colliton said. "[Crawford] didn't see a couple of them. There's a deflection off a glove, but they give themselves a chance for the puck to go in.
"We passed up some shooting opportunities, which, if you find a way to get it through and hit the net, you never know. And we had some shots but we could've had even more. We could've generated even more chances, and if you do that, maybe you change the momentum of the game, draw a penalty."
Video: COL@CHI: Compher scores on odd-man rush
They said it
"We know that we have a lot of depth in our organization, but it's not easy to just come up and play the right way. Guys have been unbelievable. Every time we have had one guy leaving [with an injury] a new guy shows up and does the job. It's a lot of confidence to know that it doesn't matter who we have, we can still play good NHL games." -- Avalanche forward Pierre-Edouard Bellemare
"We know we can play better, we know we need to play better. They're a good team and we're going to need to respond [Saturday] with a better effort. We weren't terrible, we just weren't good enough." -- Blackhawks coach Jeremy Colliton
Need to know
Blackhawks defenseman Duncan Keith left in the second period with a groin injury. "We know he won't travel," Colliton said when asked for an update. "More than that, no." … Avalanche forward Andre Burakovsky (upper-body injury) missed his first game this season. … Makar leads NHL rookies with 26 points (eight goals, 18 assists) in 25 games.
Blackhawks: At the Colorado Avalanche on Saturday (9 p.m. ET; ESPN+, ALT, NBCSCH, NHL.TV)
Avalanche: Host the Chicago Blackhawks on Saturday (9 p.m. ET; ESPN+, ALT, NBCSCH, NHL.TV)
Video: MacKinnon powers Avalanche past Blackhawks