The BBC Shanghai ship has left the northern French port of Cherbourg, carrying 25 tonnes of reprocessed nuclear waste, after getting approval from local officials.
It is due to arrive by the end of the year in New South Wales state.
The radioactive waste aboard is from spent nuclear fuel that Australia sent to France for reprocessing in four shipments in the 1990s and early 2000s.
This process involves removing uranium, plutonium and other materials and storing the remaining substance in glass containers.
The Australian Nuclear Science and Technology Organisation hit back at environmentalists' warning, saying in a statement that, "the ship was selected by [France-based nuclear company] Areva, and after a full inspection carried out by both French maritime safety authorities and by the French nuclear safety regulator on Wednesday 14 October, the ship's seaworthiness was confirmed and certified."
Greenpeace and the French environmental campaign group Robin des Bois (Robin Hood) had called for the shipment to be halted.
Jacky Bonnemains of Robin des Bois told RFI that the "vitrified waste has traces of plutonium and uranium and other long-life radio nucleatites which are are enough to put in
danger coastal populations, or fish or other sea life, if the ship capsizes, collides with another ship or if there is a fire."
She says that the ship is known in ports around the world, from Vladivostok to Punta
Arenas to Honolulu, and also in Europe, for having many deficiencies, when she is calling in the ports. They are technical: Improper firefighting and lack of extinguishers, which is important when a ship is carrying hundreds of tonnes of fuel and radioactive waste.
Bonnemains added that "the French and Australian authorities are not strong enough to go against the decision taken by Areva. And cancelling the chartering of the ship would have provoked political and technical difficulties."
A senior lawmaker in the Green party, Denis Baupin, also weighed in, saying on Twitter "Areva, almost bankrupt, are using a dustbin ship to carry waste, without any serious inspection!"
Australia has the largest deposits of uranium in the world. Although it does not have a domestic nuclear energy program, the nuclear industry is pushing the energy source as a way to reduce greenhouse gas emissions.
The country does, however, generate nuclear waste from medical technology.
Successive governments have, unsuccessfully, attempted to find a new dumping site for this waste.