Police say the accident was reported at 12:29 p.m. Monday in the 2800 block of Montchanin Road just south of the intersection of Smithsbridge Road.
The crash involved a 2004 Saturn Ion and a 2003 Honda Civic.
Police say the female drivers, ages 21 and 25, were trapped in their vehicles.
The 21-year-old driver was flown to Christiana Hospital with serious leg injuries.
The 25-year-old woman was also transported to Christiana Hospital with hip, leg and knee injuries.
The investigation caused the closure of Montchanin Road Monday afternoon.
