The crash happened on the A1 near Hillsborough at about 08:00 BST on Friday.
The road is closed in both directions at the junction between the Ballygowan Road and the Dromore Road.
Police said drivers should expect delays in the area for a number of hours.
Traffic is being diverted through Hillsborough.
The woman is the second person to lose their lives on Northern Ireland roads in the space a few hours.
A man in his 50s died after his motorbike was in collision with a roundabout on the Comber Road in Newtownards shortly before midnight.