Erik Karlsson had a goal and an assist to increase his season total to 98 points for the Sharks (22-40-16), who had a four-game point streak end (3-0-1). Kaapo Kahkonen allowed four goals on 19 shots before being pulled 8:06 into the second period. James Reimer made 10 saves in relief.
"They're the defending Stanley Cup champions and they're just better than we are," San Jose coach David Quinn said. "At the end of the day, talent caught up to us over a two-game series. That's all that happened, really."
Karlsson gave the Sharks a 1-0 lead at 15:43 of the first period, scoring from the slot on a rebound of Kevin Labanc's shot from the blue line.
Rantanen tied it 1-1 at 16:45 on the rebound of a shot by MacKinnon, who skated between two defenders for a backhand. It was his 50th goal of the season.
"I'm sure it's probably been on his mind here for a little bit," Colorado coach Jared Bednar said. "We're happy for him. He's put in the work to become an elite goal-scorer in this league, and then to see him hit 50 is pretty special."
Rantanen put the Avalanche ahead 2-1 at 2:32 of the second period when Evan Rodrigues carried the puck from behind the net and passed to Rantanen, who scored on a backhand.
MacKinnon extended the lead to 3-1 at 7:19 before Rantanen completed his sixth NHL hat trick to make it 4-1 at 8:06.
"[I] play with good teammates and good linemates," Rantanen said. "They're making good plays for me to score, like today. It's just fun to share it with them, for sure."