The Bills, who were winless entering Sunday's game in Minnesota, closed as consensus 17-point underdogs to the previously unbeaten Vikings. They are the 15th underdog of 17 or more points to win a game in the Super Bowl era and the largest underdog to pull off an upset since the Washington Redskins knocked off the Dallas Cowboys 24-17 as 17.5-point underdogs on Dec. 3, 1995.
There had been 24 favorites of 17 or more points since that game; each of them prevailed. The Bills ended that streak, storming out to a 27-0 halftime lead behind rookie quarterback Josh Allen and an opportunistic defense. Allen gave the Bills a 7-0 lead five minutes into the game with a 10-yard touchdown run. It was the first lead of the season for Buffalo.
Bills cornerback Tre'Davious White could be heard yelling "You like that?!" as he came off the field after the game, in an apparent re-enactment of Vikings quarterback Kirk Cousins' famous catchphrase while in Washington.
Asked about it later, White was more subdued, saying, "It's the first win of 2018 for the Buffalo Bills, so of course, it's a big deal. Like I said, y'all like that? Y'all like that, huh?"
The Vikings' six rush attempts were their fewest since the AFL-NFL merger, according to the Elias Sports Bureau. The only other time since 1970 that Minnesota attempted fewer than 10 rushes was Dec. 18, 2016, against the Colts (nine attempts).
NFL favorites of 17 points or more fell to 145-15 straight up in the Super Bowl era.
The upset proved costly for some Las Vegas gamblers. On Sunday morning, a bettor at a William Hill sportsbook in Nevada placed an $18,000 money-line bet on the Vikings at odds of -1,800 for a chance at netting $1,000.
The Westgate SuperBook told ESPN it took a $9,000 money-line bet on the Vikings at -2,000 odds shortly before kickoff. That bet would have won a net $450.
On the other side, there were 255 money-line bets placed on the Bills to pull the upset at 10-1 odds at William Hill books in Nevada and New Jersey, the largest a $1,000 wager that earned a $10,000 profit.
The Bills are also responsible for two of the four largest point-spread upsets. They defeated the New York Jets as 20-point underdogs in 1968 and beat the New England Patriots as 18.5-point favorites in 1977.
In addition, the Bills authored the largest comeback win in history, overcoming a 32-point deficit to defeat the Houston Oilers in a 1993 wild-card playoff game.
"[The spread didn't affect us] at all," White said of Sunday's outcome. "Like I said earlier this week when y'all interviewed me, I think ever since I've been here, every game I've been in, we've been the underdogs. It's nothing new to us. We just go out and play.
"The analysts can pick whoever they want, but we gotta go out and play. So at the end of the day, it's all just football. We executed a little bit better today."
ESPN's Mike Rodak and ESPN Stats & Information contributed to this report.