The Repsol Honda rider set a benchmark time of one minute 39.783 seconds to finish over a quarter of a second up on home favourite Ben Spies, who impressed for Yamaha.
Spies' team-mate Jorge Lorenzo, who leads the championship by 23 points from Pedrosa, took third place in 1min 40.502secs, while Yamaha Tech 3's Andrea Dovizioso, Pedrosa's team-mate Casey Stoner and Britain's Cal Crutchlow (Yamaha Tech 3) completed the top six.
Elsewhere, Hector Barbera was taken to Indianapolis Methodist Hospital after suffering multiple fractures in a heavy crash at the final turn during Friday morning's opening practice session.
The Pramac Racing rider suffered fractures to the fifth, sixth and eighth dorsal vertebrae and will remain in hospital for observation overnight.
Barbera has been replaced by Toni Elias for the remainder of the weekend.
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