The bus broke through a barrier and plunged off the road near railway tracks in the district of Mestre, which is connected to Venice by a bridge.
It had been rented to take tourists between Venice and a campsite in the nearby Marghera district, reports say.
Venice Mayor Luigi Brugnaro said a "huge tragedy" had taken place.
"An apocalyptic scene, there are no words," he said on X, formerly Twitter.
The incident happened at about 19.45 local time as the bus was reportedly taking tourists back to the campsite.
