The bus, which was carrying mainly junior high school students, was struck by the train in Millas about 18 kilometres west (11 miles) of the city of Perpignan, close to the Spanish border.
A rescue operation was under way.
The head of security for the Pyrenees area, where the collision took place, confirmed the accident involving a train travelling west from Perpignan to the town of Villefranche de Conflent.
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The bus was transporting mainly junior high-school students.
The BFMTV channel said it was struck in the rear.
President Emmanuel Macron in a tweet wrote: "All my thoughts for the victims of this terrible accident involving a school bus, as well as their families. The state is fully mobilised to help them."
Prime Minister Edouard Philippe and Transport Minister Elisabeth Borne were on their way to the scene from a meeting in the south-central city of Cahors.
"It's a terrible event," Education Minister Jean-Michel Blanquer said, expressing "profound sadness".
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