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Chances were scarce in the first quarter, with only a Blair Walsh field goal separating the two teams after the opening 15 minutes.
Quarterback Teddy Bridgewater and Kyle Orton both had their struggles in the second, with the Bills picking up the opening touchdown through Watkins after the Vikings passer had thrown an interception.
Walsh ensured that the visitors remained ahead going into the break, kicking his second field goal of the game just before the half time.
Both team's defenses continued to hold firm in the third quarter, while only another Walsh kick added to the half-time scores before the two-minute warning in the fourth quarter.
It looked like the Vikings had done enough when the home side needed 20 yards on fourth down with just over a minute to play, but Orton made a long pass to Scott Chandler to keep their hopes alive.
Chris Hogan managed to haul in a catch at the one-yard line, leaving the Bills with five seconds on the clock to find the potentially game-winning touchdown.
Watkins lost his defender, and took the catch in the corner of the endzone to complete the Bills comeback, giving them their fourth win of the season.
The result leaves the Bills second in the AFC East, one win behind the New England Patriots, while the Vikings sit bottom in the NFC North with just two wins from their first seven games.