The accident happened in Biloxi, Mississippi at around 2.15pm local time.
The CSX train was headed east while the bus was headed north.
Biloxi city spokesman Vincent Creel said emergency responders were still removing injured people from the bus more than 30 minutes after the crash.
More details to come.
Miller said the bus was coming from Austin, Texas and heading to an unknown destination in Mississippi. Officials said the crossing has flashing lights and crossing gates.
The tour bus had been travelling from Austin in Texas when it crashed shortly after 2pm (8pm United Kingdom time), and it is thought those on board may have been heading to one of Biloxi's eight casinos.
Visual evidence and eye witness testimony indicate the train "t-boned" the bus on the tracks. Charter buses often carry patrons to casinos in Biloxi, but Creel says he doesn't know where this bus was headed.
Biloxi Police Chief John Miller confirmed the fatalities in a press conference Tuesday afternoon. It is unclear why the bus was stopped on the tracks. "My first instinct was trying to get people to tell them to get off the bus, and by the time I got there the train had already hit it, dragged it to where it is now".