Trent Green threw for 368 yards and three scores as the Chiefs remained the league's lone unbeaten team.
Dante Hall had another long punt return to set up a score, and the defense recorded its league-leading 19th interception as Dick Vermeil's club became the ninth team to start 9-0 since the NFL-AFL merger of 1970.
The Chiefs will play their next three games against teams with losing records. They had 27 points at the half.
Cleveland closed within 34-20 late in the third quarter, but Green sealed the contest with a fourth-quarter scoring strike to Eddie Kennison. He completed 29-of-42 passes, and found Holmes, Kennison, and tight end Tony Gonzalez seven times each.
James Jackson had 17 carries for 66 yards for the Browns (3-6), who had given up just 130 points before this contest.