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."