The loss pushed Anaheim's winless skid to 11 games but gave the club points on back-to-back nights. The Ducks fell to 23-45-12 on the season and 12-22-4 on home ice.
Frank Vatrano scored twice for Anaheim, part of a night on which he would set a new career high in points in his first year as a Duck. Adam Henrique and Brett Leason also scored. Cam Fowler, Trevor Zegras, Troy Terry, Kevin Shattenkirk and Ryan Strome tallied assists.
Rookie netminder Lukas Dostal was in strong in net for Anaheim in his 22nd career NHL appearance, stopping 41-of-46 Colorado shots.
Mikko Rantanen and Nathan MacKinnon each scored twice for the Avalanche, who won their fifth straight game and created a two-point lead on Minnesota for first place in the Central Division. J.T. Compher also scored. Goaltender Pavel Francouz made 19 saves.
Colorado buried the only goal of the opening period, as Compher found free space at the backdoor and swatted home a pass from Valeri Nichushkin on the second try from the side of the net.
Compher's goal was his 17th of the season, one shy of his career-high set last year. The 28-year-old pending unrestricted free agent owns personal best totals in points (52), assists (35), power-play goals (five), power-play points (14) and game-winning goals (three).
Nichushkin has assists in back-to-back games and later in the night clinched his first 30-assist season in the NHL.
The Avs would add to the advantage late in the second period, taking a two-goal lead, albeit one that lasted just 77 seconds, on a terrific individual effort by Rantanen. One of the few Avalanche stars to avoid missing time to injury this season, the All-Star winger danced inside the Ducks defense from left wing, eventually using the backhand to beat Dostal to the glove side.
Rantanen, who recently became the third Finnish-born NHLer to score 50 goals in a season (joining Teemu Selanne and Jari Kurri), has 12 points in his last four games (6-6=12). His 54 goals on the year are 17 clear of his previous career high and rank third among league leaders, behind only Connor McDavid and David Pastrnak.
With three points on the night, Rantanen clinched his first career 100-point season, a feat teammate Nathan MacKinnon accomplished earlier this month. MacKinnon and Rantanen are the Avalanche's first 100-point duo since the club's first season in Colorado (1995-96).
With the primary assist, defenseman Sam Girard secured his first 30-helper season in the NHL. Girard tallied points in each of his three matchups with Anaheim this season.
Suddenly down 2-0 in the second half of the season's final back-to-back, the Ducks would require only 4:11 to pull back even, taking advantage of consecutive Colorado puck management miscues.
The first came as the Avs failed to get the puck fully out of the zone, with Vatrano keeping it in as the last second and then finishing a centering feed from Zegras on left wing.