Spain's Pedrosa covered the 28-lap, 118.048km circuit on his Honda in 47 minutes, 31.615 seconds while American Ben Spies, who began the race on the pole, finished second in 47:35.190.
Pedrosa said he was pleased with his ride and the way he handled the hot temperatures on Sunday.
"It was very, very warm out there. You know, you didn't cool down in the 45 minutes you're out there," said Pedrosa. "The track was slippery, the bike always starts to be very greasy. So many crashes because of the bumps and the track temperature.
"It was very important to be focused in every corner and make no mistake with the bumps, especially at the end when the tires are more damaged."
Jorge Lorenzo of Spain, who won the race here last year, had his worst finish of the year when he placed third.
Lorenzo, well on his way to a world championship, finished over 12 seconds behind the winner in a bid for his eighth victory of the year.
Tragedy struck during the first race of the day at the Indianapolis Speedway when 13-year-old racer Peter Lenz died after crashing and being run over by another young competitor.
Lorenzo saw Pedrosa gain some ground in the series. With six races remaining, Lorenzo has accumulated 251 points. Pedrosa is second at 183 and Italian Andrea Dovizioso is third with 126.
Spies, starting on the pole for the first time in his rookie season, held the lead for six laps.
Pedrosa completed an inside pass on the front straightaway of lap seven and slowly pulled away from the American. His biggest advantage was 5.622 seconds after the 19th lap.
"We can't complain," said Spies. "We had a good start and led some laps. Didn't set the world on fire, but we had a good pace. It just wasn't fast enough."
Sunny skies and a temperature of 92 degrees Fahrenheit greeted the riders at the start of the race. On the opening lap, Dovizioso rode his Honda from fourth to second place with Nicky Hayden dropping to third.
Pedrosa passed Hayden on the next lap. Marco Melandri of Italy crashed on the third lap when Lorenzo, who had started second, slipped to fourth.
Pedrosa passed Dovizioso for second in turn one of the fourth lap and from then on he and Spies battled for the lead.
The Spaniard trailed Spies by .888 seconds after four laps, cut the difference on each of the next two laps before moving ahead. His lead after seven laps was .015 and steadily grew on 10 consecutive laps.
He had the fastest lap of the race on lap at one minute, 40.896 seconds.
"I must not be disappointed, but I'm not happy with my ride," said Lorenzo, who had finished first or second in every race this year. "I didn't feel so good with my physical condition. The third lap I was tired and I was not able to make the same pace as in practice."
Lorenzo also discussed the tough track conditions.
"The track was so slidey and also the bumps were difficult," he said. "I almost crashed in some corners, so I prefer to finish third and not to take so many risks."
Among those who had a problem was Casey Stoner, whose streak of five consecutive podium finishes ended when he lost control of his front and crashed on the eight lap.
"I am very disappointed. It was a nothing crash, but obviously it was enough to leave me out of the race," said Stoner. "We struggled to find front-end feel in the corners. It is a real shame because we had good pace and I think we could have been on the podium"