The Ducks cut it to 3-2 at 13:05 when a backhanded centering pass by Pavel Mintyukov went off the leg of Killorn and was redirected into the net.
Samuel Girard was awarded a penalty shot at 14:36 after he was hooked from behind by Jackson LaCombe on a breakaway, but Gibson made the save.
MacKinnon scored into the empty net with 1:19 left for the 4-2 final.
MacKinnon leads the NHL with 55 points (14 goals, 41 assists).
The Ducks went 0-for-5 on the power play, the last opportunity coming with 3:53 remaining in the game.
"We’ve got to find ways to score," Killorn said of the power play. "Whether it’s just getting more shots from the top, which can create more, but it can’t be a momentum killer for us. Even if we don’t score, we have to try and gain some momentum on it."
Anaheim came out quicker than Colorado, outshooting the Avalanche 12-5 in the scoreless first period.
"Sometimes it's going to take 20 minutes on the road in the second game of a back-to-back for the boys to wake up," Wedgewood said. "We have a standard and the first period wasn't it."
After spending 27 of the past 35 days on the road, the Avalanche are looking forward to playing five of their next six in Denver.
"It's nice to go home now, play a little bit more home games from now on," Mikko Rantanen said. "We've been on the road a lot the last month."
NOTES: Colorado improved to 13-1-1 in its past 15 games against Anaheim. ... The Avalanche have nine comeback wins in their past 21 games. ... Colorado is 9 for 9 on the penalty kill in the past two games. ... Rantanen had two assists to increase his point streak to eight games (four goals, 11 assists). ... Colorado’s defensemen have combined for 91 points (16 goals, 75 assists) to lead the NHL. ... Avalanche forward Jere Innala had two blocked shots and three hits in 7:09 of his NHL debut.