The 21-year-old man had chained himself to train tracks near the northeast city of Nancy when the train passed by, severing one of his legs.
Emergency treatment was carried out at the scene but medical staff were unable to save the activist.
Authorities said the accident happened in the town of Avricourt, where a group of eight people had gathered along the Paris-to-Strasbourg line to wait for the arrival of the nuclear transport train.
“After coming out of a corner at reduced speed, the train was apparently confronted with the group, which moved out of the way with the exception of one person, who was hit,” a police spokesman said.
The police did not reveal the man’s identity saying only that he was aged 21, probably from the Meuse region in France’s east, and belonged to a protest group.
Prior to the confrontation at Avricourt, the train was delayed for two hours near Nancy as police removed two protesters who had also chained themselves to the railway lines.
A member of the activist organisation Sortir de Nucleaire (Nuclear Out) said about a dozen protesters had been involved, all of them French nationals.
“It appears that the demonstrators had not put in place safety measures destined to warn the convoy of their presence,” he said.
The train had been bearing 12 containers of treated nuclear waste from the French plant at La Hague to Gorleben in northern Germany and eventually reached its destination 24 hours after its departure.
It was the seventh such consignment to be returned to Germany since 1996.
The German Greens Party, which forms part of the German governing coalition, said it was stunned by the fatality and that a thorough investigation of the incident was expected.
The party called on demonstrators not to risk their lives with their campaign actions.
Thousands of German protesters were on hand to confront the arrival of the waste shipment in Dannenberg, temporarily blocking the train before it set off for the final leg of its journey to Gorleben.
Germany, which has no nuclear re-processing facilities, sends spent fuel rods to La Hague for treatment before returning to the country for storage.