Sammy Blais cut it to 3-1 at 16:17 after a turnover by Colorado's Patrik Nemeth. Blais shot from along the goal line to Grubauer's right after Krug's shot ricocheted to him.
Brayden Schenn made it 3-2 at 10:07 of the third period, putting in the rebound of Tyler Bozak's shot on a power play after Avalanche forward Nazem Kadri was assessed a match penalty for a hit to the head against Blues defenseman Justin Faulk, who left the game.
The Blues also lost Bortuzzo at 9:24 of the second period with an upper-body injury after a hit by Avalanche forward Tyson Jost.
"The League will look at those hits, and they'll do what they have to do," said Blues coach Craig Berube, who didn't have an update on either player. "You're down to four D, and that's in a playoff game. That's difficult, but I thought guys did a good job."
Bednar said MacKinnon and Landeskog " got the guys together on the bench, had a little chat" after the penalty.
"And off they went to answer the bell and get us a couple big goals," Bednar said.
MacKinnon pushed the lead to 4-2 at 15:25, but Mike Hoffman scored 15 seconds later with a shot from the left circle to make it 4-3 at 15:40.
"I won't say patient, but we've got to understand that we have to play a certain way against this team and we can't wait until the second period to do it," Berube said. "Pucks got to go in deep, they got to go 200 feet, we've got to be a good forecheck team and then we've got to shoot pucks. I thought we passed up shots again in the first period, and then we allow them to come out of their zone way too easy and they get these rush attacks against us and they get opportunities off of it."
Brandon Saad scored into an empty net to make it 5-3 with 2:09 left, and MacKinnon completed his hat trick with an empty-net goal with 12 seconds remaining for the 6-3 final.
NOTES: MacKinnon's is the first hat trick in the Stanley Cup Playoffs for the Avalanche since Valeri Kamensky in Game 5 of the Western Conference Quarterfinals against the Chicago Blackhawks. … Donskoi's first goal was the fastest from the start of a playoff game in Colorado history. … The Avalanche have a 19-game point streak at home (18-0-1). … Blues defenseman Vince Dunn skated Wednesday but missed his 13th straight game. He is recovering from an upper-body injury.