The Vikings ranked 31st in total yards allowed (6,608) and finished the season with a negative point differential (−3), the first time this had been done by a team with at least 12 wins.

On January 10, 2022, the Vikings fired head coach Mike Zimmer, who had led the team to two NFC North titles and three NFL playoffs appearances in his eight years in charge.

[19] On February 16, 2022, former Los Angeles Rams offensive coordinator Kevin O'Connell was named the 10th head coach in franchise history.

[20] The Minnesota Vikings fired tenth-year general manager Rick Spielman on January 10, 2022, who most notably led the organization to draft Adrian Peterson, Percy Harvin, Harrison Smith, Teddy Bridgewater and Anthony Barr, among other draftees.

[21] Initially, Adofo-Mensah and Kansas City Chiefs Executive Director of Player Personnel Ryan Poles were the finalists for the general manager position.

On May 4, the NFL announced that the Vikings would play the New Orleans Saints at Tottenham Hotspur Stadium in London, United Kingdom, on October 2, as part of the league's International Series.

[24] On May 9, the NFL announced that the Vikings would play at the Philadelphia Eagles at 7:30 p.m. CDT on September 19, as part of ESPN's Week 2 Monday Night doubleheader.

The Vikings' week 15 matchup was against the Indianapolis Colts, one of the second-placed teams from the American Football Conference (AFC) whom they were not originally scheduled to play in 2022.

Cousins then threw an interception, but this time the defense was able to hold Buffalo to a field goal, keeping the score at 17–7 as the game ticked into the second quarter.

The Vikings then drove down to the Bills' 2-yard line, but a tackle for loss on Alexander Mattison, followed by an offensive pass interference call against T. J. Hockenson meant they had to settle for a field goal.

Midway inside the Buffalo half at the two-minute warning, the Vikings were faced with a 3rd-and-1 situation, but were unable to convert on successive passes from Cousins to Jefferson and then K. J. Osborn, resulting in a turnover on downs.

The Vikings began the second half with the ball, but after big gains by Jefferson and Dalvin Cook, Cousins threw an interception to Dane Jackson.

On the ensuing possession, the Vikings worked the ball downfield and made it into the red zone on a 21-yard catch by Adam Thielen, before Cousins took it down to the 3-yard line on a 15-yard scramble.

Following an incompletion to Jefferson, fullback C. J. Ham ran the ball into the end zone, only for Greg Joseph to hit the upright with the extra point, leaving the Vikings down 27–23.

The Vikings were soon faced with a 4th-and-18 situation going into the two-minute warning, only for Cousins to complete a 32-yard pass to Jefferson, who caught it one-handed between the hands of the defender, Cam Lewis, getting them into Bills territory.

The Bills quickly made their way into Vikings territory thanks to runs by Allen, and back-to-back seven-yard catches by Diggs got them comfortably into field goal range.

The two teams then exchanged punts before Vikings quarterback Kirk Cousins threw an interception deep in his own territory that Julian Blackmon returned 17 yards for a touchdown.

The Vikings eventually had to punt, and with four minutes left in the half, the Colts drove the ball downfield and kicked a 27-yard field goal to go into the break up 33–0.

They opened the fourth quarter with a 20-yard completion from Cousins to Justin Jefferson, and an unnecessary roughness penalty on Rodney Thomas II added another 15 yards.

The Vikings made their way downfield, helped by another unnecessary roughness penalty for a hit on Jefferson by Stephon Gilmore, only for Cousins to throw another interception when targeting Reagor on a deep route that the receiver appeared to give up on.

The Vikings won the toss ahead of the extra period and elected to receive the ball, but their opening drive stalled following a Cousins sack and an offensive holding penalty against guard Ezra Cleveland.

After a 6-yard run by Cook, Cousins completed passes to Osborn, Hockenson and Jefferson to get the Vikings down to the Colts' 27-yard line with 20 seconds left to play, and a delay of game penalty against Odenigbo moved them 5 yards closer to the end zone.

Despite the Colts calling a timeout in an attempt to ice the kicker, Joseph's kick was successful, giving the Vikings a 39–36 win and completing the biggest comeback in NFL history.

The Giants responded with a score of their own as Jones completed five out of five pass attempts and also ran for 14 yards, culminating with a 7-yard touchdown throw to Isaiah Hodgins.

The reprieve allowed the Vikings to continue the drive, which culminated with another touchdown catch for Hockenson from 15 yards out, putting the hosts back in front 17–13 as the game entered the fourth quarter.

The Giants were then able to reduce the deficit to a single point; after the turnover, they only managed to go 18 yards, but Gano was successful on a 55-yard field goal attempt.

A 4-yard run from Dalvin Cook and an 8-yard completion to K. J. Osborn gave them a first down, before Cousins found Jefferson over the middle for a 17-yard touchdown to extend the lead to eight points with just over 3 minutes to play.