The motorway remains closed northbound between junctions 9 and 7, with the M50 eastbound and other roads also affected.
The crash also caused a major fuel spillage.
Ambulance crews were called to the northbound carriageway of the M5 between junctions 8 and 7 at 4.31am, but it quickly became apparent that nothing could be done to save the driver and they were confirmed dead at the scene.
It is understood that the collision involved four lorries and the road would remain closed 'for several hours'.
West Midlands Ambulance Service sent two ambulances, three paramedic officers, their Hazardous Area Response Team, and a MERIT trauma doctor to the scene.
A West Midlands Ambulance Service spokesman said: “On arrival we discovered a lorry driver who had suffered serious injuries in the collision.
"Sadly, it quickly became apparent nothing could be done to save them and they were confirmed dead at the scene.
“Ambulance crews worked closely with fire and police colleagues to carefully cut a second lorry driver, a man, free from his vehicle, a process which took approximately 90 minutes.
“Following treatment at the scene for potentially serious injuries, he was transported to Queen Elizabeth Hospital, Birmingham for further treatment.”
It was one of two crashes on the northbound carriage in the early hours, after a HGV and a people carrier crashed on the M5 south of Worcester at 2.50am. Three ambulances and two paramedic officers attended the scene.
A West Midlands Ambulance Service spokesman said: “On arrival we discovered six patients from the car.
“A man, who was a rear seat passenger, was treated for potentially serious injuries and taken to Worcester Royal Hospital.
“The driver and a second rear seat passenger, both men, were treated for injuries not believed to be serious before being taken to Hereford County Hospital on the same ambulance. Three further patients were discharged at the scene.”
Drivers face major delays as West Mercia Police say the M5 closure "will be in effect for several hours" and drivers are advised to take alternative routes.
The #M5 northbound is now closed from J9 (#Tewkesbury) to J7 (#Worcester) due to the serious collision between J8 (#M50) and J7. We've moved the closure back to J9 due to delays on the original diversion route. More info on the new diversions here: https://t.co/ZcVgw2qYsj pic.twitter.com/TF3tYWuJbT— National Highways: West Midlands (@HighwaysWMIDS) August 3, 2022
Travel firm Inrix has also reported that 100 litres (22 gallons) of diesel have been spilt on the road.