The suspected gunman was identified as Arif Uka, a Kosovo citizen from the northern town of Mitrovica. He has been taken into custody.
Officials said the bus driver and a passenger were killed, and one person suffered serious wounds and another light injuries. All of them were airmen, according to a U.S. Air Force Europe spokeswoman.
The shooting remained under investigation. The names of the individuals are being withheld for 24 hours after notification of the next of kin.
The military has several major bases in the Frankfurt region.
The Associated Press reported an uncle of the suspected shooter is a German Muslim who worked at the Frankfurt airport.
In an interview with The Associated Press in Kosovo, 70-year-old Rexhep Uka said the suspected gunman, Arid Uka, was born and raised in Germany after his parents moved there from Kosovo about 40 years ago.
The uncle says Arid is a pious Muslim whose grandfather was a religious leader at a mosque in the village of Zhabar, near Mitrovica, Kosovo.
The Frankfurt airport refused to comment on whether the suspect worked there.
The Associated Press contributed to this report.