The Australian set his fastest time in the final minutes, and after a brief red flag period caused when Hector Barbera fell heavily at T16.
The Spaniard was riding for Pramac Ducati in a bid to prove his fitness, having broken his leg just four weeks ago. He had to be stretchered off the circuit and was taken to the medical centre and then the local hospital with chest and back pain. Pramac have 2010 Moto2 champion Toni Elias on standby.
Honda had controlled the session up until Barbera's incident, with Pedrosa clear on a 1m42.192s.
Stoner then managed to shave around two tenths off that after the resumption, dipping into the 1m41s.
No other rider was able to get within five tenths of a second of the Australian, with Ducati's Nicky Hayden leading the rest of the pack, 0.547s down.
His compatriot Ben Spies, facing possibly his final home MotoGP race - his future remains undecided - was fourth, a further tenth of a second down the road.
Stefan Bradl (LCR Honda) and Alvaro Bautista (Gresini) put the gloss on a strong session for Honda by finishing fifth and sixth respectively, ahead of Yamaha riders Cal Crutchlow (Tech 3) and championship leader Jorge Lorenzo.
Crutchlow was the only other man to fall during the session, losing his bike early on at T14. He recovered and was able to return in the final minutes, securing seventh.
That left him four spots above team-mate Andrea Dovizioso, with Lorenzo, Valentino Rossi and Barbera separating the pair.
Indianapolis GP FP1 times:
1. Casey Stoner, Repsol Honda Team, 1:41.925
2. Dani Pedrosa, Repsol Honda Team,+0.181
3. Nicky Hayden, Ducati Team, +0.547
4. Ben Spies, Yamaha Factory Racing, +0.611
5. Stefan Bradl, LCR Honda MotoGP, +1.102
6. Alvaro Bautista, San Carlo Honda Gresini, +1.270
7. Cal Crutchlow, Monster Yamaha Tech 3, +1.370
8. Jorge Lorenzo, Yamaha Factory Racing, +1.387
9. Valentino Rossi, Ducati Team, +1.420
10. Hector Barbera, Pramac Racing Team, +1.811
11. Andrea Dovizioso, Monster Yamaha Tech 3, +1.820
12. Yonny Hernandez, Avintia Blusens, +2.403
13. Aleix Espargaro, Power Electronics Aspar, +2.789