Patriots quarterback Tom Brady was picked off twice, while Chiefs playmaker Alex Smith dominated the contest with three touchdown passes and 248 yards gained from 20 completed plays.
Brady, meanwhile, was largely ineffectual - gaining 159 yards from 14 completed passes before being replaced late in the game.
Both sides sit with 2-2 records a quarter of the way through the regular season.
Patriots coach Bill Belichick had only overseen one worse defeat in 14 years, as the Chiefs entered the end zone five times.
Jamaal Charles crossed for a six-pointer in the first quarter with a two-yard run, to begin a 27-point run from the hosts in Kansas.
Charles then caught a five-yard pass from Smith in their only other TD of the half, before the Chiefs were denied a third right on the line of the end zone late in the second quarter - only for rookie kicker Cairo Santos to drill a 22-yard field goal to make it 17-0 at the interval.
Despite only having three catches for 16 yards gained for the match, Charles was involved in the scoring again as he caught an eight-yard throw from Smith as the Royals put the erroneous Patriots to the sword.
Santos kicked his second field goal of the contest, this time from 31 yards, before New England finally got on the board when Brady found Brandon LaFell with a 44-yard pass.
However, Kansas City did not let up - Smith passing to Travis Kelce for a TD before Husain Abdullah intercepted Brady and returned for a 39-yard TD.
Jimmy Garoppolo replaced Brady late on, and threw a consolation TD pass to Rob Gronkowski.