A witness who was on the train, named as Barbara, said "it was a very violent crash - it seemed as if the train would derail".
The two deaths at a local hospital were both 11-year-old girls, the AFP reported.
Another 19 people were reportedly injured on the bus, including seven seriously, during the incident near Pergignan, local news website L'Independent reported.
The bus was struck by the train in Millas about 18 kilometres west of the city of Perpignan, close to the Spanish border.
The official said, according to the Press Association, how witnesses said that barrier was down at the time of the crash on Thursday (14 December) and there would be an investigation to see if the crossing worked properly.
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A United Nations panel of experts said it is extremely unlikely that the Houthis could manufacture such missiles on their own. Its own leaders have said it is helping the Houthis. "That's what Iran is actively supporting".
Transport Minister Elisabeth Borne called the crash a "terrible accident" and Education Minister Jean-Michel Blanquer was due to visit a counselling centre set up at the Christian Bourquin College on Friday.
President Emmanuel Macron reacted to the news by tweeting: "All my thoughts are with the victims of this bad accident of a school bus and with their families".
The French prime minister Edouard Phillipe arrived at the scene around 8pm.
The French interior ministry said that 95 emergency workers are now at the site alongside 15 police units. "The state is fully mobilised to come to their aid".