The four-metre male orca was first spotted two weeks ago near the river's mouth, but made its way dozens of miles upstream towards the city of Rouen.
A plan to guide it back to the sea using sound stimuli failed, and experts concluded it was seriously ill.
The authorities had been preparing to euthanise the animal but activists say it died of natural causes.
Environmental campaign group Sea Shepherd tweeted that the orca's corpse was found at 11:48 local time (09:48 GMT) on Monday.
Reuters quoted the group's leader Lamya Essemlali as saying that by Monday it was "a ghost of an orca" and died before any attempt could be made to put it to sleep.
The activists said they were staying with the body to make sure it was not hit by a ship, which would compromise the autopsy.
A salvage team is expected to recover the body and move it to shore.
The orca was seen for the first time on 16 May between Honfleur and Le Havre near the mouth of the Seine.
Experts concluded that it was critically ill with mucormycosis - a new disease found in marine mammals - when it failed to respond to sound stimuli, displaying a lack of alertness and disorientated behaviour.
The disease, which begins as a skin infection, spreads to the heart, lungs and brain, and in this case was thought to be far advanced.
Local officials hope to use the autopsy to carry out further research on the disease, which has been seen in North America but not yet in Europe.
Orcas, members of the dolphin family, can be found in a variety of marine environments, ranging from the Arctic and Antarctic to tropical waters.
There have been rare sightings in the English Channel and it is unusual to see one in a river.