The collision occurred at about 2:45 p.m. Friday in Hillsborough, about 10 miles north of Princeton.
Police say a 1993 Toyota Camry driven by 73-year-old James Draiss of Belle Mead crossed a grass median before hitting the bus.
Draiss was pronounced dead at Somerset Medical Center. A girl in the car was airlifted to Robert Wood Johnson University Hospital.
Her identity was not released and no information was available on her condition.
Police say two of the 13 Hillsborough High School students on the bus suffered minor injuries.
Investigators believe Draiss may have suffered some type of medical problem prior to the collision.