Jordan Binnington, who stopped 81 of 85 shots over the first tow games of the series, was injured just 6:45 into the game after he was knocked over by teammate Calle Rosen and Avalanche forward Nazem Kadri, who was skating hard for a rebound.
"I just see a loose puck, really", Kadri said. "I mean, I was kind of just sitting behind him and just tried to poke it with my stick, and I think their defenseman kind of collided with me and pushed me into him.
"So, you know, had that not been the case, I don't think I would have hit him at all. It's a loose puck. I'm just trying to bang it in."
The Blues led 1-0 at the time of Binnington's injury.
"It's always tough", captain Ryan O'Reilly said. "Obviously, 'Binner's' the heart and soul, playing unbelievable, but I think it kind of took the momentum away and took us a little too long to kind of get it back going again.
"We're a deep team, and we could have done a better job of getting the momentum back and adjusting."
Artturi Lekhonen scored twice, Kadri had a goal and an assist, and Darcy Kuemper made 29 saves for the Avalanche.
"I thought we were a little tentative out of the gate", said coach Jared Bednar. "And then as we kind of got playing a little bit, just every minute got a little better and got ourselves into the game.
"Not the ideal start you want. You could sense a little nervousness, but I give our guys a lot of credit for playing through that. Darcy came up with big saves for us when we needed them tonight, because we had some breakdowns, especially at the end of the second."
Colorado lost defenseman Samuel Girard to a broken sternum after he was checked hard behind his net by Blues forward Ivan Babrashev 1:42 into the first.
"Looking back on it, it's a heavy collision", Bednar said. "He just catches him in a bad spot, but it was a legal check, to be honest with you.
"He kind of goes in on his head side, but he got a lot of body there. [Girard] was turned the wrong way, and he went in awkward, and it was a heavy check.
"Unfortunate, but to honest, it was a legal check."
O'Reilly had a goal and an assist for the Blues. Ville Husso, who was replaced by Binnington in Game 4 of the first round, made 19 saves.
'I liked our game", coach Craig Berube said. "I thought we checked well. We did a lot of good things right. A lot of good things.
"The effort was there. I thought we played a solid game. Yeah, there were some stretches there where we didn't maybe get pucks in deep enough for some stretches in the second and third period, but that's hockey.
"I thought we worked them pretty good overall, but obviously we didn't get enough goals. So we've got to do a better job."
Story of the game
Colton Parayko opened the scoring less than four minutes into the game as his slap shot from a faceoff win by O'Reilly deflected in off of the snapped stick of Colorado defenseman Devon Toews.
Logan O'Connor, who was scratched from the first two games of this series, tied the game after Josh Manson gloved down a pass by Darren Helm and as the Blues tried to knock it away, O'Connor chipped a high shot glove side past Husso.
"I found out this morning, seen it on the lineup sheet", O'Connor said. "It was nice to get the opportunity tonight."
Kadri put the Avalanche in front with 6:22 left in the second as he redirected a shot from Cale Makar six seconds after a power play had expired.
Lehkonen made it a 3-1 game as he beat Husso short-side from a two-on-one after Brayden Schenn had missed on two chances moments earlier.
With 30 seconds remaining in the period, O'Reilly cut it to a one-goal game, scoring on a rebound in the slot.
Gabriel Landeskog restored Colorado's two-goal lead, shooting into an empty net as Husso wasn't able to make it back into position in time.
Lehkonen added a second empty-netter with 52 seconds left for the final margin.