It happened shortly after midnight on the 100 block of Airport Road near Churchman's Road in New Castle.
Police tell Action News the driver of a BMW crossed the center line and struck a Lincoln Towncar.
The impact of the crash trapped both drivers inside of their vehicles.
Medics transported the driver of the BMW to Christiana Hospital in critical condition.
A man and a woman and their 9-year-old son in the Towncar were also taken to Christiana Hospital with non-life-threatening injuries.