Colorado (51-24-7) finished the regular season one point ahead of the Dallas Stars and will face the Seattle Kraken in the Western Conference First Round of the Stanley Cup Playoffs.
"To win the division, I know it doesn't really mean a ton usually, but I feel like this year it means a little bit more. We battled hard to be here," MacKinnon said. "It will be tough, very tough.
"[The Kraken] work hard. They've given us trouble this season, so we're going to [have to] be at our best to beat them."
MacKinnon had four points, and Devon Toews had a goal and an assist for the Avalanche. Alexandar Georgiev made 18 saves for his 40th win of the season, tying Linus Ullmark of the Boston Bruins for the League lead.
"I think these guys put their heart and soul into this season," Colorado coach Jared Bednar said. "To be able to sort of accomplish our regular-season goal of winning the division and securing home ice, if we're fortunate enough to make it into the second round, it's a feather in their cap, no question. And we should feel good about our game going into the playoffs."
Kiefer Sherwood had two goals, and Luke Evangelista scored for Nashville (42-32-8). Kevin Lankinen made 30 saves.
"It's the NHL. Your job is to be able to win and be competitive, regardless of what the circumstances are, and to me that's what I think the coaches and players, together, embraced," Predators coach John Hynes said. "You can't look for a different situation and want something different and complain about what's going on. You have to find what are the actions and attitudes and mindsets that we have to have to give ourselves a chance to be successful in this situation, and that was the challenge."
Toews gave Colorado a 1-0 lead just 28 seconds into the first period when his wrist shot from the blue line caromed off the leg of Nashville defenseman Dante Fabbro and past Lankinen.
MacKinnon made it 2-0 at 3:20. He stick-handled his way to the net from the left boards and fired the puck far side for his 40th goal of the season.
"He was a man on a mission tonight, you could tell," Bednar said of MacKinnon. "They scored their first two shifts, almost scored again on their third shift. He was a part of everything we generated on the offensive side of it tonight. For him to come out on a night like this and have the legs that he did and play with the determination that he played with and then get the hat trick is pretty special."