It was an all Spanish podium as Honda team mate Dani Pedrosa was second and Jorge Lorenzo third for Ducati.
Italian Valentino Rossi, making a remarkable comeback barely three weeks after suffering a broken leg, finished fifth on his Yamaha after lying second earlier on.
Team mate Maverick Vinales of Spain, who started on pole, was fourth and compatriot Aleix Espargaro of Aprilia sixth.
Briton Cal Crutchlow was in contention for a top-six place but crashed and had to retire on lap 17.
Marquez started the race in fifth position after crashing in qualifying and had a slow start but quickly gained on his rivals, taking the lead from Lorenzo on the 16th lap and charging to his fifth title of the season.
"It was a difficult race. At the beginning I didn't have the feeling. I tried to come back with the feeling but even in the last part of the race I didn't feel great. I struggled more than other years here. But it's great," Marquez said.
Lorenzo came close to claiming his first win of the season but faded as the race entered the final stages.
"It's a pity to lose the victory by not so much. In the last 10 laps we needed more grip in the rear. With the medium (tyres) of Dani and the hard of Marc I couldn't follow them. Anyway, I'm happy with this third position," Lorenzo told reporters.
By winning with four rounds remaining Marquez was able to take a clear lead in the standings as Andrea Dovizioso, previously the joint leader, managed only seventh place.
Marquez, who also won in San Marino two weeks ago, now has 224 points, Dovizioso 208 and Vinales 196.
The next race is the Japan Grand Prix in Motegi on Oct. 15.
(Reporting by Steve Tongue and Aditi Prakash; Editing by Clare Fallon and Christian Radnedge)
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