MacKinnon's tally was also his 97th point of the campaign, which matches his career best from 2017-18, and the 400th point (154 goals, 246 assists) of his NHL career.
Video: EDM@COL: MacKinnon pots 40th goal, gets 400th point
The Cole Harbour, Nova Scotia, native, who was selected first overall by the Avalanche in the 2013 NHL Draft, became the first member of his draft class to reach the 400-point milestone.
At 23 years and 213 days old, MacKinnon is also the second youngest player in Avalanche/Quebec Nordiques franchise history to reach the 400-point mark. Sakic holds the record as the youngest to tally his 400th at 23 years, 135 days old.
"You have always seen from Day 1 that he has got that game break mentality, and he can just take over," teammate Gabriel Landeskog said of MacKinnon. "There are not a lot of players that can get the puck wherever really on the ice and all of a sudden, the building, the energy, just you can hear it, and everybody just expects something great to happen.
"You have always seen that with him. You have always seen the skill set that he has and his skating ability, but it started last year--that is when he really started taking off and taking his game to a different level. He is not slowing down any time soon. He is a lot of fun to watch and great to see him score 40 tonight."
Video: Gabriel Landeskog after the Avs' 6-2 win vs. Oilers
The goal was the first of four Colorado tallies in the second period, all of which came in a span of 7:08, the fastest four markers the Avs have recorded this season. It is the seventh time this year that the Avalanche has lit the lamp four or more times in a single frame.
"We would have liked to start the game like we started the second period, just with that fire and come out with everybody skating and everybody contributing and things like that," said Landeskog. "We end up falling behind for whatever reason… but I am real happy with the way we played start of the second and to finish the game. I thought we really started taking over."
Colorado found the back of the net six or more times in a contest for the 12th time this year, the most such performances in a single campaign since the 1996-97 club (also 12 games with six or more goals).
The Avalanche is now 7-0-2 in its last nine games and 14-5-3 its previous 22 outings. This stretch includes a season-long, five-game home winning streak, and Colorado is 10-2-1 in its last 13 contests at Pepsi Center.
KERFOOT STREAK EXTENDED: Alexander Kerfoot scored twice for his second multi-goal game of the year, the fifth in his NHL tenure, and extend his point streak to a career-long six games. He has totaled eight points (four goals, four assists) during the stretch.
The 24-year-old's first tally stood as the game-winner in the contest, the first game-winning marker of his career.
Video: EDM@COL: Kerfoot taps in go-ahead goal for Avalanche
"I think he has been outstanding. He was a difference maker again tonight, a difference maker yesterday," head coach Jared Bednar said of Kerfoot.
The second-year forward now has 42 points (15 goals, 27 assists) through 76 contests this season.
PLUS-5 NIGHT FOR BARRIE: Tyson Barrie finished with two points (one goal, one assist) to bring his season total to 58 and surpass his previous career high of 57 points in 2017-18. It's the most points by an Avalanche defenseman since Ray Bourque tallied 59 during the 2000-01 campaign.
Barrie also finished with a career-high plus-5 rating, the best plus/minus rating by a Colorado player in a game since Nathan MacKinnon was plus-5 on March 2, 2018 versus the Minnesota Wild. It is also tied for the third-best plus/minus rating in a game in Avalanche history (since 1995-96). Barrie is the first Colorado defenseman with a plus-5 rating since Rob Blake on March 19, 2006 at San Jose.
"Barrie was phenomenal tonight," said Bednar. "Again, he just continues to drive our team offensively. He is getting up into plays, great decision making, good competitiveness, those guys have really stepped up for us here lately."
400 GAMES FOR NIETO: Avs forward Matt Nieto assisted on Kerfoot's first tally of the game to record his 19th helper of the year in his 400th NHL contest.
"When I first got in the league, you never know how long your career can be," Nieto said after the game. "To make it to 400, it is a big accomplishment that I am proud of. I have played with a lot of great teammates along the way and had good coaches too, credit to them as well."
Video: Matt Nieto on the Avs' win and his 400th NHL game
The San Jose Sharks selected him in the second round (47 overall) in the 2011 NHL Draft, and he played his first 221 outings with the Sharks before Colorado claimed him on waivers on Jan. 5, 2017.
The Long Beach, California, native has 130 points (54 goals, 75 assists) in his career and 23 points (four goals, 19 assists) through 62 contests this season.
VARLY IN NET: Goaltender Semyon Varlamov was between the pipes for the first time since March 15, and he made 27 saves to earn his 20th win of the season.
The Russian netminder now has six 20-win campaigns in his career (all with Colorado), ranking second in Avalanche history to Patrick Roy (eight 20-win seasons).
"I got a lot of faith in Varly. I think Varly has played really good here before [Philipp] Grubauer kind of established himself and took the net over recently," said Bednar. "He was playing well, and it is just a tough back-to-back. You get in late and your getting ready to play, and we still got two more games to win. To me, it was a game that I thought Varly could come in the net and win for us."
Video: EDM@COL: Varlamov denies Kassian from in tight
MIKKO RANTANEN UPDATE: The Avalanche's second-leading scorer, Mikko Rantanen, missed his sixth game with an upper-body injury that he sustained on March 21 at the Dallas Stars.
"There is hope, I don't know how much, but there is hope," Bednar said on if Rantanen could return before the regular season concludes on Saturday at the San Jose Sharks.
Rantanen has recorded a career-high 87 points (31 goals, 56 assists) in 74 contests this season for the Avs.
AVALANCHE NOTES: Colorado wrapped up its season series with Edmonton and finished 2-1-0 against the Oilers.
The Avs matched their largest come-from-behind victory of the season, erasing a two-goal deficit (five times - last: Jan. 12 at Toronto, trailed 2-0, won 6-3).
The contest was also the second half of a back-to-back for the Avs, their last of 11 such sets in 2018-19. Colorado finished 5-3-3 in both the first and the second half of these sets.
The Avalanche finished 1-for-3 on the power play and has scored a man-advantage tally in four straight home contests and five of its last six overall outings, going 6-for-18 (33.3 percent) in that span.
Matt Calvert picked up his 15th assist of the season, matching his career-high totals from 2013-14 and 2017-18 (both with the Columbus Blue Jackets). His 26 points this season are also a career high.
Gabriel Landeskog registered two assists to bring his season total to 40, a new career high that eclipses his previous best of 39 helpers in 2013-14. He has five points (one goal, four assists) in three games since returning from injury.
Erik Johnson notched his 17th assist of the season, his highest assist total since notching 30 helpers during the 2013-14 campaign.