After switching routes overnight to avoid anti-nuclear protests, it arrived in the French border city Strasbourg just after midday to switch locomotives and take on board a fresh escort of German riot police.
It then crossed the Rhine at Kehl just outside the city, again surprising activists, who had prepared protests on another route further north.
Many thousands of demonstrators had begun gathering at a number of sites on the German side of the border, vowing to block the shipment, which is returning German waste for storage after it was treated in France by the Areva group.
Nuclear power raises huge passions in Germany, amid divisions over whether it should be abandoned, and a previous waste shipment sent over in 2008 was blocked for 14 hours by protesters, amid violent scenes.
"The train is under surveillance. We don't want it moving in secret, as Areva seems to want," said Laura Hameaux, a spokeswoman for the pressure group "Sortir du Nucleaire" (Get out of Nuclear).
Anti-nuclear campaigners had planned a series of demonstrations along the original route of the 14-wagon train carrying 123 tonnes of nuclear waste, stabilised by being melted and mixed into glass cylinders.
They had been expecting the train to head north to the French border town of Lauterbourg before crossing the frontier, but authorities apparently diverted it to avoid protesters trying to block the tracks.
A helicopter flew above the train, which included three carriages filled with riot police as well as the special trucks for the waste.
Large numbers of officers were also deployed along the route from the processing plant near Cherbourg in Normandy, as protesters tried to take radiation readings in towns like Peltre as the train passed through.
Areva insists that the load of waste, originally created during power generation in Germany, is not unusual for the industry.
On Friday, activists chained themselves to train tracks a few hundred metres from Caen station in northwestern France, holding up the train for several hours before it resumed its journey to Gorleben in Germany.
Police arrested seven people, while three of those chained to the rails were taken to the hospital "because they were burned during the extrication," a police source said, adding that the burns were "not serious."
The protesters chained their arms inside metal tubes and concrete in order to make it difficult to be released.
"This nuclear convoy, the most radioactive ever, exposes the population to excessive risks," a spokesperson for Sortir du Nucleaire said. "There is a risk to lives in the short term in case of an accident, but also a long-term risk to their health."
Areva spokesman Christophe Neugnot called criticism from groups such as Greenpeace "a smokescreen for anti-nuclear protestors to hide the fact that nuclear energy is taking off again in almost all European countries."
He dismissed concerns about possible leaks in transit, describing the train as a "fortress on wheels. The containers would survive a train hitting them at full speed."
Areva has also rejected the "most radioactive" tag, insisting the cargo is not as radioactive as the last load of waste they shipped back to Germany.
Around 30,000 demonstrators were expected to oppose the train's arrival in Germany, where around 16,000 police have reportedly been mobilised to deal with protests.
Environmentalists also say the intermediate storage facility at Gorleben is not up to the task of safeguarding the waste.
German lawmakers last week approved a bill extending the life of the country's 17 reactors by 12 years, although they were due to come offline in 2020. Opinion polls show that most Germans were against parliament's decision.
The convoy is the 11th of its kind. Almost 16,000 police were deployed in Germany for the previous shipment in 2008.