The crash occurred yesterday shortly after 2 pm (local time) at a railroad crossing in the Gulf Coast city of Biloxi, police chief John Miller said.
"It's a terrible, chaotic scene right now but we have it under control," Miller said at a news conference.
He said the charter bus had travelled from Austin, Texas, and was probably headed to a casino in Biloxi.
Three people died at the scene and a fourth person died later, fire chief Joe Boney told the local Sun Herald newspaper.
Craig Robinson, who said he witnessed the crash, told the Sun Herald that the bus appeared to be stuck on the train tracks for about five minutes before the train plowed into it.