It happened around 5:00 p.m. on Kennett Pike in the area of Old Gatehouse Road near Winterthur.
Police say the driver of a 2007 Chevy Silverado was traveling north when the vehicle crossed the center line and struck a 2005 Nissan Sentra, sending the car off the road and into a utility pole.
The three people inside the Sentra became trapped inside the vehicle and had to be pulled from the wreckage by firefighters.
The 22-year-old male driver of the Sentra was flown to Christiana Hospital for serious injuries to the head and torso.Two passengers in the Sentra were also taken to the hospital. The 25-year-old male rear passenger suffered head, leg and pelvic injuries. The 59-year-old female front passenger suffered chest and possible head and internal injuries.
Meanwhile, the driver of the Silverado, a man in his 30s, refused medical attention at the scene. Police also issued him a ticket for driving without a valid license, failing to have insurance and driving on the wrong side of the road.
The cause for the crash is still under investigation.