It happened just before 11:45 p.m. Saturday at K Street and Hunting Park Avenue.
When officers arrived, they found the driver of a gold Lexus dead in the car.
A passenger, who had been ejected, died at the hospital.
Officials say four people were inside the other vehicle involved, a black Jeep Cherokee.
Two of them were also taken to the hospital.
Their conditions are unknown.
Police are now investigating whether alcohol played a role in the crash.