The Predators (47-23-10) would have moved into the lead with a win but remain one point (105-104) behind the St. Louis Blues, who lost 1-0 to the Winnipeg Jets. The Blues and Predators have two games remaining.
It was the first home game for the Avalanche (37-31-12) since they were eliminated from Stanley Cup Playoff consideration on Saturday.
"Nobody should be happy," Predators coach Peter Laviolette said. "We lost the game. We needed to win a hockey game. It didn't happen. Unfortunate turn of events happened on the ice. We walked out of here without the points tonight. It's difficult, it's hard to stomach right now."
The Predators, who have lost four games in a row, outshot the Avalanche 42-23.
"It's really frustrating," Nashville goalie Pekka Rinne said. "We’ve had a bunch of these games of late where we have more shots and overall play a really good game and the result ends up like this.
"I don’t think there’s one reason. I think everyone cares a lot. We know what we’re playing for, there’s a lot on the table. We have the chance to be the top seed in our division and all of those things, so I don’t know what it is. We just have a lot of things going against us right now.”
Avalanche rookie Joey Hishon, playing in his 11th NHL regular-season game, broke a 2-2 tie with his first goal at 7:06 of the third period after being promoted to the third line because Dennis Everberg sustained a shoulder injury. Predators defenseman Roman Josi lost the puck to Marc-Andre Cliche, who passed to Hishon. He weaved his way into the Nashville end and sent the puck by Rinne's stick.
"It was a great play by Cliche to force the play to me," said Hishon, who also won all six of his faceoffs. "It was a really good neutral zone forecheck to turn that puck over. I was lucky enough to take it over the blue line and to get a shot on net and was lucky enough that it went in.
"It was amazing. I had a lot of adrenaline running through my veins, so it was good to get that first one. To get it in a win is even bigger. I couldn’t stop smiling after. There were 11, 12 minutes left in the game, so I had to try and focus on my breathing and come back down to Earth."
Hishon, 23, was the Avalanche's first-round pick (No. 17) in the 2010 NHL Draft. He missed the entire 2011-12 season because of a head injury and was limited to nine games in 2012-13 with the Lake Erie Monsters in the American Hockey League.
"It's awesome to see a guy like that who's been through a few injuries and through a tough time," Avalanche captain Gabriel Landeskog said. "You can tell that he never gave up, he always wanted to develop and keep going. I think he's shown a lot these last few weeks."
Nashville tied the game 2-2 on a power-play goal by Ryan Ellis at 1:20 of the third period. He took a shot from above the circles through traffic and past goalie Semyon Varlamov for his second goal in two games and ninth of the season.
The Predators thought they scored 18 seconds later when Josi's shot got past Varlamov, but the goal was wiped out when it was ruled that Paul Gaustad interfered with the Avalanche goalie, who appeared to fall after losing an edge.
"I got an explanation, which didn't match with what we saw," Laviolette said. "It's disappointing. We're battling for home ice, everybody is battling for something in the League. It's just a frustrating, disappointing turn of events right there."
Colorado couldn't get much of anything going offensively until late in the second period when Jarome Iginla and Ryan O'Reilly scored nine seconds apart for a 2-1 lead to tie an Avalanche record for two fastest goals.
"They're a good team, they play really well and they played us hard all year," O'Reilly said. "The last time we were in their building they embarrassed us (5-2 on Feb. 24). We have to have pride and we played with that tonight."
O'Reilly followed at 15:41. Landeskog passed to O'Reilly in the high slot for a shot that eluded Rinne to the stick-side for his 17th goal. O'Reilly has seven goals and eight assists in the past 12 games.
"Our players deserve a lot of credit," Avalanche coach Patrick Roy said. "Our guys gave a great effort, they played hard and just found ways to score the two goals."
The Predators, who took the first nine shots of the game, grabbed a 1-0 lead at 5:02 of the opening period on a goal by Calle Jarnkrok. Matt Cullen had the puck at the side of the net when he passed to Jarnkrok just inside the right circle near the hash marks. He shot the puck by Varlamov's left arm.
"Our goal is to be playing our best hockey going into the playoffs and I don’t think we are right now," Predators defenseman Shea Weber said. "There’s too many mistakes right now. We’re doing a lot of things well, but those little mistakes are just biting us right now."