The coach hit several vehicles before smashing through a parapet and toppling down a steep slope near the town of Avellino, in the Campania region.
At least 10 people have been injured, some of them seriously, Italian media report.
The coach was taking about 50 people, including children, back to Naples following a pilgrimage, reports say.
The cause of the accident is not clear.
TV footage showed smashed vehicles on the flyover and shrouded bodies lined up by the side of a road.
The driver of the coach is said to be among the dead.
“The situation is critical,” leading fireman Pellegrino Iandolo told Italian television.
“Our men are working to save as many lives as possible.”
A police spokesman told the French news agency AFP that the number of victims could not yet be confirmed.
“We are still pulling people from the vehicle,” he said.
He added that the Naples-Bari motorway had been closed to traffic because of the accident.
Reports say the bus smashed through a guardrail on the flyover and dropped 30 m (98 ft), coming to rest in heavy undergrowth.
The injured have been taken to hospitals in Avellino, Salerno and Nola, Ansa said.
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