Part of the A49 near Harewood End was closed on Friday evening (January 10) following the crash which involved two vehicles.
A spokesperson for West Midlands Ambulance Service said that three ambulances, a paramedic officer, a trauma team and a doctor responded to the scene.
“The driver of one car, a man, sustained potentially life-threatening injuries in the collision.
“The team of medics worked to administer trauma care and specialist pre-hospital treatment before he was blue-lighted to Queen Elizabeth Hospital Birmingham for further trauma care.
“Two other casualties were assessed but didn’t require hospital treatment and were discharged on scene,” they said.
A spokesperson for the fire service said one male casualty in his 80s was extricated by fire crews, whilst both vehicles were made safe.
Three casualties were then handed over to the care of the ambulance service, with an air ambulance also in attendance.
West Mercia Police have now launched an appeal for information after the incident.
A spokesperson said: “At around 5.05pm two vehicles, a Silver 4×4 Suzuki and a grey Ssangyong pickup, were travelling in opposite directions along the A49 between Hereford and Ross-on-Wye.
“The cars collided, leaving one driver – a man in his 80’s – with serious and potentially life-changing injuries. He was taken to hospital where he remains.
“The driver of the second vehicle suffered minor injuries. No one else was injured.
“Anyone with information or dashcam footage of the collision, or in the moments before, is asked to contact PC Tom Milton. You can call him on 07773 049588 or email tom.milton@westmercia.police.uk.”