Fire crews freed the casualty who was trapped inside the overturned car after the crash with an on-call ambulance in Plungington Road at around 9.30am.
The injured driver was then rushed to the Major Trauma Ward at Royal Preston Hospital with life-threatening injuries.
The ambulance driver and a colleague were not injured but are said to be shaken by the incident.
Pictures from the scene show the overturned silver car with its roof torn open where firefighters rescued the injured driver.
Police are at the scene and Plungington Road remains cordoned at the junctions with Adelphi Street and Aqueduct for investigation.
A North West Ambulance Service spokesman said: “At around 9.30am this morning, an ambulance responding to an incident on blue lights has been involved in a collision with another vehicle as it was travelling through the junction of Plungington Road and Aqueduct Street in Preston.
“The motorist in the other vehicle has been transported to Royal Preston Hospital and is being treated for major trauma.
"The two ambulance crew members are shaken but unharmed.
“We’re helping the police with their investigation to determine the full circumstances of the incident and hope the motorist makes a full recovery.”
The Plungington Road closure is causing congestion in the area, including along Aqueduct Street, Ripon Street and Brook Street.
A police spokesman added: “We were called to Plungington Road, Preston, at 9.28am today (June 17) to a serious collision involving a car and an ambulance.
"Emergency services are on scene and work is ongoing to free the casualty from the car.
"We have not established the seriousness of their injuries yet.
“A road closure is in place in Plungington Road at the junctions with Adelphi Street and Aqueduct Street.”
Anyone with information should call police on 101, quoting log 0357 of June 17, 2022.