Sissons scored two goals in the first period, and completed his second regular-season NHL hat trick when he tipped in Kyle Turris' shot on a power play with 3 seconds left in the second period to make it 3-1. Ryan Hartman made it 4-1 with an empty-net goal with 2:54 left in the third.
Sissons, who had one goal in the first 14 games, has scored eight goals in 10 regular-season games against the Avalanche.
[WATCH: All Predators vs. Avalanche highlights]
"Everybody has a team or two they have success against and feel good against," Sissons said. "Fortunately for me it's a team in our division. They are always tough games, like playoff games, and I like playing in those games. Maybe that's it."
Nick Bonino had three assists, and Pekka Rinne made 24 saves for the Predators (12-3-0), who have won four games in a row, 11 straight against the Avalanche in the regular season and all seven road games this season.
Predators coach Peter Laviolette said he put Sissons, Bonino and Hartman on a line for their defense, so their offense was a bonus.
"[Sissons] played really well tonight," Laviolette said. "That line did a terrific job. Colton had a big night."
Video: Enterprise Hat Trick: Sissons nets second NHL hatty
Matt Calvert scored, and Semyon Varlamov made 30 saves for the Avalanche (7-5-3), who have lost four games in a row (0-3-1) and five of six. Colorado had two goals overturned by video review.
Sissons gave Nashville a 1-0 lead at 13:39 of the first period. Bonino was at the right side of the net when he slid the puck to Sissons on the opposite side for a tap-in.
"Kind of a gift on the back door," Sissons said. "It was just kind of sitting there for me."
The Predators made it 2-0 at 17:21 when Roman Josi passed to Sissons in the right circle for a shot that beat Varlamov to the blocker side.
"Josi kicked it out to me and I just placed a nice shot, fortunately," Sissons said. "The [third one], a little bit of luck on a tip-in."
An apparent goal by Colorado's Ian Cole at 1:29 of the second was overturned following a video review after Nashville requested a Coach's Challenge. Samuel Girard brought the puck outside the zone on a spin move, causing the play to be offside.
The Avalanche closed to 2-1 at 7:08 when Calvert scored on a power play. Girard took a shot from the blue line and Calvert deflected it for his first goal of the season. Nathan MacKinnon had an assist, his 200th in the NHL.
"It felt great to contribute offensively," Calvert said. "I was trying too hard, I think. It was a great shot by [Girard] and I got a stick on it. Sometimes you need the first one to go in like that."
Video: NSH@COL: Calvert tips Girard's shot past Rinne
A goal by the Avalanche's Colin Wilson at 7:39 of the third was overturned when it was determined that Alexander Kerfoot was offside following another Coach's Challenge by the Predators.
"Great calls by our video guys, but it was offsides," Laviolette said. "That's what rules are for. They were great calls by our guys in the back room and they were close, too, but they were adamant they were offsides, and you have to be sure. There was no question about [challenging them.]"
Said Avalanche coach Jared Bednar: "Tape-to-tape passes we're throwing into guys' skates even when there aren't players in-between them, going offside on goals, that's part execution, slows down our pace, slows down the tempo of our game.
"The two goals getting called back to me is just another aspect of our lack of execution."
They said it
"Focus, we know what we have to do. We come to the rink ready to play. There is less matching going on, we just roll the lines with no last change." -- Predators forward Nick Bonino on their road success
"They are a very good hockey team and I think we put ourselves in a hole there early. We didn't play well enough from the drop of the puck. We spotted them way too much, let's just say that. You know, we came back, we put some pressure on them, but too little, too late." -- Avalanche defenseman Ian Cole
Need to know
Avalanche forward Mikko Rantanen was held without a point for the third time this season. He leads the NHL in assists (19) and points (24) … Rinne has a 24-7-2 record against Colorado … Josi has five points (two goals, three assists) in a four-game point streak. … The other regular-season hat trick for Sissons was on Jan. 5, 2017 in a 6-1 win at the Tampa Bay Lightning. He also had a hat trick in the Stanley Cup Playoffs, against the Anaheim Ducks in a 6-3 win May 22, 2017 in Game 6 of the Western Conference Final.
Predators: At the Dallas Stars on Saturday (2 p.m. ET; FS-SW, FS-TN, NHL.TV)
Avalanche: At the Winnipeg Jets on Friday (8 p.m. ET; TSN3, ALT2, NHL.TV)
Video: Sissons' hat trick powers Predators to 4-1 win