Bills quarterback Josh Allen passed for 315 yards and three touchdowns, adding 59 yards and a score on the ground, while Buffalo's top-ranked defense got after Patrick Mahomes and the Chiefs in a handy road win.
The Bills scored 17 consecutive points in the second quarter to move into a commanding 24-13 lead at half-time, but their momentum was then stalled by a 62-minute delay during the break due to thunderstorms in the area.
When the game finally did resume, Buffalo continued to dominate proceedings, with Mahomes picked off on back-to-back possessions in the third quarter, with the first of them returned for a 26-yard touchdown by Micah Hyde.
Rookie pass rusher Greg Rousseau snagged the second pick off a rattled Mahomes, who also coughed up a late fumble. The Kansas City quarterback finished with 272 passing yards and 61 on the ground, but was unable to prevent the Chiefs slipping to a second-straight home defeat and to 2-3 on the season. The Bills, meanwhile, sit atop the AFC East with a 4-1 record.
It was Kansas City who took an early lead in the contest as Harrison Butker fired through a 31-yard field goal to cap a lengthy, 17-play opening drive from the home side.
The Bills answered with a touchdown on their opening series - Allen in for a nine-yard score - before the Chiefs then fumbled the subsequent kick-off, but with Buffalo unable to add any points off of the turnover.
Mahomes led another lengthy Chiefs drive, capped with a five-yard touchdown to Byron Pringle to again see them nose ahead, only for Buffalo to once more answer back with seven of their own, Allen finding Emmanuel Sanders from 35 yards for the first of his two scores on the day.
Tyler Bass added a field goal on Buffalo's next series, before Allen connected with tight end Dawson Knox on a stunning 53-yard strike following off the back of Kansas City turning the ball over on downs when going for it (and failing, Mahomes incomplete to Travis Kelce) on 4th-and-5 from the Buffalo 32-yard line.
Butker was at least successful on KC's next series with a kick from 54 yards as the clock ran down on the first half, the Chiefs going into the break down by 11 at 24-13.
The hosts had a chance to regroup during a lengthy interval as local thunderstorms caused an hour-long delay to the second half. But, when the game did finally resume, Buffalo's defense continued to dominate and Allen continued to impress with some flashy plays - including one which saw him leap over an onrushing Kansas City defender.
Hyde' pick six saw the Bills streak further clear, and though a Mahomes touchdown to favourite target Kelce early in the final quarter of the contest briefly had the home support hopeful, Allen answered right back with his second TD toss to Sanders to effectively put the game away.
The Chiefs (2-3) host the Washington Football Team (2-3) next Sunday, with both playoff teams from last year looking to kick-start their seasons after sputtering starts. The Bills (4-1), meanwhile, will feature on Monday Night Football as they travel to Tennessee to take on the Titans (3-2).
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