The 25-year-old Spaniard had started fourth after collecting a three-place grid penalty in qualifying but seized the lead on the opening lap before disappearing into the distance at the Circuit of the Americas.
It was the four-times MotoGP champion's 10th successive win in the United States in the top category, with the others coming at Laguna Seca and Indianapolis.
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"My strategy was just start, push and that's it," said Marquez, who shrugged off boos from the crowd reacting to a champion whose on-track clashes with rivals have been a talking point of the season.
"I didn't have confidence to battle so I was pushing from the beginning and just go away, open the gap...in Spain they will be happy."
Maverick Vinales, who started on pole for Yamaha, finished second and 3.560 seconds behind his compatriot while Italian Andrea Iannone was third in his first podium with Suzuki.
Andrea Dovizioso finished fifth for Ducati and regained the championship lead with 46 points after three races, the Italian now one clear of Marquez with Vinales third on 41.
Britain's Cal Crutchlow, who had led the standings after winning in Argentina, crashed his LCR Honda with 12 laps to go and failed to score after rejoining in 22nd place and finishing 19th.
Marquez had a lonely race, challenged only briefly by Iannone before pulling clear to live up to his fame as "King of COTA", and that will have come as a relief for both him and Honda.
He had been nearly eight seconds clear with a lap to go before easing up at the end.
"It's quite noisy, eh? But it's funny. Don't worry," he said of the crowd's reaction.
In Argentina, he and Italian great Valentino Rossi collided -- with the Yamaha rider accusing the champion of "destroying" MotoGP by what he considered dangerous behaviour on track.
"I'm scared on the track when I'm with Marquez," Rossi had said.
Marquez did himself no favours in Saturday's qualifying either, crashing before returning on a spare bike and then picking up the grid penalty for blocking Vinales who was on a hot lap.
Spaniard Dani Pedrosa finished seventh for Honda, two weeks after fracturing his wrist and undergoing surgery.
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