Twenty-one youngsters from Our Lady and St Patrick's High School were taken to hospital after the crash on Renton Road in Dumbarton.
Their vehicle collided with a Vauxhall Corsa at around 8.40am. The 27 year old man driving the car was airlifted to Glasgow's Queen Elizabeth University Hospital (QEUH) in a serious condition.
A number of pupils were being treated for minor injuries after the incident, according to West Dumbartonshire Council. They were taken to the QEUH and the Royal Alexandra Hospital in Paisley.
A council spokesman said: "Enquiries are ongoing to establish the circumstances of the crash."
Six vehicles and an air ambulance to dispatched to the scene by the Scottish Ambulance Service. Renton Road was closed between Dalreoch railway station and the slip road leading to the A82.
Inspector Adam McKenzie said: "We are still conducting enquiries to establish the circumstances of the crash and I am appealing to anyone who may have been travelling on the road and who may have information which could assist in our investigation to contact us."
Anyone with information is being asked to call road policing officers at Dumbarton police station via 101. They should quote reference number 0801 of 23rd August.