The crash happened just before 5 p.m. and involving a tractor-trailer and three other vehicles.
New Castle County Paramedics and several fire companies responded to reports of a serious accident involving an overturned tractor-trailer.
Delaware State Police said the tractor-trailer failed to stop in traffic, rear-ending a Nissan Sentra and forcing it across all of the southbound lanes of the highway.
Police said the tractor-trailer traveled on to strike a Honda and a Toyota, forcing both of those cars off of the highway and down an embankment.
The trailer ultimately overturned onto its right side, broke through a guardrail and then overturned further, coming to rest partially in the center grass median and partially in the left thru lane of northbound I-95.
Authorities confirm the driver of the Nissan, a 45-year-old Middletown man, died at the scene and the occupants of the other vehicles were all injured, some seriously.
The 9-year-old girl, who was a passenger in the Honda, was taken to A.I. DuPont Hospital for Children, where she succumbed to her injuries.
Officials said the 49-year-old female driver of the Honda was treated at the scene for significant injuries all over her body. She was taken to Christiana Hospital.
The 45-year-old male driver of the Toyota and the 39-year-old male driver of the tractor-trailer and sustained non-life threatening injuries.
I-95 southbound was completely closed for approximately 7.5 hours while the scene was investigated.
Anyone with information regarding the incident is asked to contact Sgt. D. Alexander of the Troop 2 Collision Reconstruction Unit by calling 302-365-8484.