Marquez, riding a Repsol Honda, completed the 27 laps (112.6km) in 42 minutes, 7.041 seconds, 1.803 seconds ahead of compatriot Jorge Lorenzo (Yamaha).
Italian Valentino Rossi (Yamaha) was 6.558 seconds back in third place, with Spaniard Dani Pedrosa (Honda) fourth in an action-packed race that featured several crashes.
Marquez, 21, also increased his lead in the 2014 standings, picking up 25 points to improve to a perfect 250 points for the season.
Pedrosa is second on 161 points, with seven-time world champion Rossi close behind on 157 points after 10 of 18 races.
Marquez started from pole but got away slowly and quickly fell back to fourth place as Rossi took the lead.
On the sixth lap, Rossi and Andrea Dovizioso appeared to have a little contact on a corner and, though they remained upright, both lost speed and Marquez took advantage to pass them both and take the lead.
Rossi temporarily dropped to third but surged back to regain the lead.
However, Marquez bided his time and took the lead again on the 11th lap, this time for good, gradually increasing his margin to win at Indianapolis for the second successive year.
American rider Nicky Hayden, who missed the race through injury, said Marquez was dominating the circuit because he did everything well.
“He really has no weak spots,” the 2006 world champion told Fox Sports.
“He’s won races from the back, he’s won races where he wasn’t necessarily the fastest, he’s flag-to-flag, switched bikes, started from the grid and... the thing he does more than I’ve probably seen anybody is ride on the ragged edge so much and not make many mistakes.”
(Reporting by Andrew Both in Cary, North Carolina, editing by Gene Cherry)
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