The bus was traveling northbound on the Bishop Ford Expressway at approximately 4:30 a.m. when it was hit by gunfire near 147th Street, police said.
Police said several bullets struck the bus, injuring the two people.
Traffic was shut down for approximately one hour while authorities investigated. All lanes were reopened as of 5:30 a.m.
The victims were taken to Christ Medical Center and their condition is unknown.
Sun-Times Media Wire contributed to this report.