The A38 is closed between the A61, Alfreton and B600 Somercotes.
The crash involved two lorries.
Highways England has warned that there are delays of at least 15 minutes covering several miles of the Northbound carriageway.
A Highways spokesman said: "Highways and other resources are working hard to restore normal conditions as soon as possible.
"We are now working on a substantial clean up. Traffic is very heavy northbound and traffic delays are past the A610 now."
No one in the collision has sustained serious injuries.
A police spokesman said: "We have reports of an accident on the A38 northbound between Alfreton and the M1. Please avoid the area where possible."
Exit the A38 onto the A61 and continue straight through two signalised junctions, then turn right onto B6019, Alfreton High Street. The turn right onto the B600 at the mini-roundabout and continue till you join the A38.