The A49 is shut south of Ludlow, between the roundabout with the A4117 and the A456 at Woofferton due to a crash between Sheet Island and the B4361 Overton Road.
West Mercia Police has said the road is "expected to be closed for some time".
Shropshire Fire & Rescue Service said three crews and rescue tender were at the scene after a call was received at 11.25am. West Mercia Police and West Midlands Ambulance Service are also in attendance.
A police spokesperson said: "Police received a report of a two vehicle collision on the A49 involving a lorry and a car at approximately 11.30am 24 January. The road is currently closed while emergency services deal with the collision."
A spokesperson for West Midlands Ambulance Service added: "We were called to a serious RTC involving two vehicles on the A49, Ludlow at 11.22am. Two ambulances, a paramedic officer and a MARS (Mercia Accident Rescue Service) Basics doctor attended the scene."
National Highways has issued a diversion route with motorists being warned of delays on approach to the closure and diversion routes.
Drivers heading south are being told to follow this route (indicated by the hollow circle diversion symbol on road signs):
Exit at Rocks Green and take the A4117 eastbound
At Callow Hill take the A456 westbound
Re-join the A49 at Woofferton
Meanwhile, those heading north should follow this route (indicated by the hollow tringle diversion symbol on road signs):
Exit at Woofferton and take the A456 eastbound
At Callow Hill take the A4117 westbound
Re-join the A49 at Rocks Green
As of 4pm the road was still closed with crews from all emergency services still at the scene.
West Mercia Police has appealed for anyone who witnessed the collision, or has any information or dash-cam footage which may help with the investigation, to email Pc Jackson at firstname.lastname@example.org, quoting incident 195i of 24 January.