Russell Westbrook had 32 points in 28 minutes, while Kevin Durant and sixth man Kevin Martin each had 20 points on 12 shots.
Reserve Reggie Jackson had eight points, seven assists and six rebounds in 20 minutes of play.
Denver had 21 turnovers, which the Thunder turned into 28 points.
“Just too many turnovers to those guys,” Nuggets point guard Ty Lawson said. “Turnovers to free throws, then another turnover to a 3 by KD (Durant). After that, they just ran with it.”
OKC now embarks on a six-game road trip over the next 10 days, beginning with an 8:30 p.m. game at Dallas, which has won four straight.
After that comes a rematch at Denver on Sunday night.
“I think we've just got to throw this game away (mentally),” Karl said. “We'll get some film that will hopefully show some things that we need to do better. We'll be on our home court (15-2 this season) and hopefully will have Wilson (Chandler) back.”
Chandler was out with a hip injury and did not play Wednesday night.
“Wilson could have had his best game in the NBA tonight, and we still would have lost,” Karl said. “Everybody's got to play better.”