It happened at about 5.3am this morning on the A64 westbound between A19 York Designer Outlet and the A1036 Copmanthorpe Road.
A North Yorkshire Police spokesman said: "The A64 between the A1036 & A19 junctions is currently closed in both directions following a road traffic collision.
"Please plan an alternative route."
As of 6.30am, North Yorkshire Police and Yorkshire Air Ambulance are on the scene.
The AA Traffic News said: "Road closed due to serious accident on A64 both ways from A19 (Fulford Interchange) to A1036.
"it has been closed since 05:30am. Trapped traffic is in the process of being released."
There are delays of 15 minutes in both directions.
Highways England has warned that delays are expected throughout the morning peak traffic.
Drivers approaching the closure are advised to expect disruption with extra journey time and have been warned that they may have to re-route their journey.
Traffic is currently being diverted around the incident.