It happened at around 6am today as the coach was heading to Barcelona from Valencia three hours south of the Catalan capital.
The crash happened near Freginals around 60 miles south of Tarragona.
The bus was carrying 57 passengers most of whom were students.
Interior Minister Jorge Fernandez Diaz said 28 passengers received medical treatment in local hospitals and others received first aid at the crash site.
The bus appeared to have hit the right-hand side barriers of the AP7 highway before cartwheeling across the road and slamming into the central fence, landing on its side, said Mr Jane, spokesman for Spain's north-eastern Catalonia province.
Television images from state broadcaster TVE showed the bus also crashed into an oncoming car on the opposite side of the highway.
It has been confirmed that two Irish students were onboard the bus and suffered non-life threatening injuries.
The Irish embassy said it is ready to provide consular assistance.
Catalan president Carles Puigdemont has announced two days of mourning following the coach crash.
Jordi Jane, a spokesman for the Catalonia province, said emergency rescue workers were still working to clear the wreckage that straddled the AP7 highway's central fence.
He said: "There were students on board, many of them foreign students studying in Catalonia and in Barcelona who had travelled to Valencia for the Fallas and were returning."
He added that the driver of the bus survived the collision and had been taken to a local police station.
Fernandez Diaz said the driver passed alcohol and drug tests he was given.
Anyone with concerns re Irish citizens who may have been affected should contact dfatravel on 014082000 or CRE_Emergencias on +34900400012
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