The Andretti Autosport ace clocked his fastest lap at 1m05.3519s at the end of the qualifying session which was enough to stay clear of his other opponents.
Team Penske's Will Power came in second only 0.18 second behind, while Ganassi's Scott Dixon and Hunter-Reay's teammate Marco Andretti finished respectively third and fourth.
The other members of Chip Ganassi squad Charlie Kimball and Dario Franchitti will both start from row three.
Current points leader Helio Castroneves joined James Hinchcliffe in providing the early upsets, with both men facing the prospect of starting from the back end of the field after being knocked out of the first group.
Unfortunately, BHA newcomer Luca Filippi was stripped of his two fastest laps for causing a red flag during the first qualifying phase.
Had his times been allowed to stand, the Italian would have been fourth-fastest in his group.
Qualifying results – Mid-Ohio (IndyCar)
Pos Driver Team/Engine Time Gap
1. Ryan Hunter-Reay Andretti/Chevy 1m05.3519s
2. Will Power Penske/Chevy 1m05.5359s +0.1840s
3. Scott Dixon Ganassi/Honda 1m05.7051s +0.3532s
4. Marco Andretti Andretti/Chevy 1m05.8566s +0.5047s
5. Charlie Kimball Ganassi/Honda 1m06.4415s +1.0896s
6. Dario Franchitti Ganassi/Honda 1m06.5854s +1.2335s
7. Justin Wilson Coyne/Honda 1m05.9405s Round 2
8. Simon Pagenaud Schmidt/Honda 1m05.9412s Round 2
9. Simona de Silvestro KV/Chevy 1m05.9621s Round 2
10. James Jakes Rahal/Honda 1m06.1778s Round 2
11. Tristan Vautier Schmidt/Honda 1m06.3379s Round 2
12. EJ Viso Andretti/Chevy 1m06.4071s Round 2
13. James Hinchcliffe Andretti/Chevy 1m06.2198s Group 1
14. Sebastien Bourdais Dragon/Chevy 1m06.1856s Group 2
15. Helio Castroneves Penske/Chevy 1m06.2280s Group 1
16. Takuma Sato Foyt/Honda 1m06.1989s Group 2
17. James Davison Coyne/Honda 1m06.2839s Group 1
18. Oriol Servia Panther/Chevy 1m06.2109s Group 2
19. Josef Newgarden Fisher/Honda 1m06.5334s Group 1
20. Tony Kanaan KV/Chevy 1m06.2537s Group 2
21. Sebastian Saavedra Dragon/Chevy 1m07.0895s Group 1
22. Graham Rahal Rahal/Honda 1m06.4002s Group 2
23. Ed Carpenter Carpenter/Chevy 1m07.4107s Group 1
24. Luca Filippi Herta/Honda 1m06.8757s Group 2