The suspects, aged 27 and 35 and from the Birmingham area, were arrested on suspicion of rape and are being held in custody.
The two sexual assaults happened within a few hours.
The initial attack was in a secluded part of Birmingham’s Witton railway station, not far from Aston Villa’s football stadium, between 8pm on Tuesday evening and 2am on Wednesday morning.
At around 2am on Wednesday, the girl left in a disorientated state via the station entrance.
As she walked away she flagged down a vehicle. She was raped a second time in the car of the man who stopped.
Police are still looking for a man in connection with the second attack. He is described as being about 5ft 6in, thick set and with large biceps.
In an update on Saturday morning, DCI Tony Fitzpatrick from British Transport Police said: “Overnight there have been significant developments after we released CCTV images of two men we would like to speak with.
“I’d like to thank the public and the media for the overwhelming support in sharing this appeal.”
DCI Fitzpatrick added: “Both these arrests relate to the first incident at Witton station on Tuesday evening this week.
“Our investigation into the second incident in the vehicle continues at a pace. The young victim was raped for a second time in a vehicle close to Witton station at approximately 2am.
“I am still looking to hear from anyone who lives locally to Witton and saw a young girl walking by herself during the early hours of Wednesday morning.
“If you saw any vehicle or any person acting suspiciously then please get in touch as soon as possible.”
Anyone with information can send a text to 61016, or call 0800 40 50 40, quoting reference 65 of 26/07/2017.
Alternatively, they can contact the charity Crimestoppers on 0800 555 111.