The incident took place near al-Mandara village in Manfalut district of Assiut province, 350 km south of Egyptian capital Cairo, officials said.
The train was heading to Aswan from Cairo and crashed into the bus carrying 60 children at the junction between the road and the railway, they said.
The children were on their way to a religious institute where they studied.
"The deaths have now reached 47. There are 13 children injured," Assiut Governor Yehya Keshk told state television.
President Mohamed Morsi has ordered authorities "to offer all assistance to the families of the victims," the state-run MENA news agency said.
In a swift move, Transport Minister Rashad al-Metini resigned, saying he "accepts responsibility" for the accident.
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Egyptian Railway Authority head Mostafa Qenawi also quit and Morsi has accepted his resignation.
Distraught relatives blocked the road at the accident site and were "collecting the remaining body parts," Osama Seddik, an eyewitness, told Egypt's Ahram Online.
Egypt's roads and railways have a poor safety record. In the worst railway disaster in Egypt, a total of 363 people were killed in February 2002 when a train heading to southern Egypt caught fire.