It happened at 7 a.m. Monday in the southbound lanes near Route 141 in Newport.
Police tell Action News the driver, identified as a 29-year-old man from Lansdale, Pennsylvania, lost control, causing the truck to hit a concrete median and overturn.
The force of the impact threw the man from the vehicle, police said.
Medics treated him at the scene for head and other injuries before rushing him to Christiana Hospital in critical condition.
He later died of his injuries.
All but one lane of I-95 South was shut down at the scene as police investigated and crews worked to clear the overturned truck.
There was no immediate word what caused the driver to lose control.
The accident remains under investigation.
The victim's name is being withheld pending the notification of his next of kin.