On the lion's Facebook page, owner Raquel Borges said: "Our beloved Ariel is gone. This is the saddest day of my life."
Further details were not immediately available.
The Facebook page created by Borges was "liked" by more than 62,500 people. The lion's death made headlines on Brazil's biggest news portals and was a top worldwide trending item on Twitter.
Borges said earlier this month that the $11,500 needed every month to pay for Ariel's treatment was coming from donations from the people who clicked the "like" button on the Facebook page and another website dedicated to him.
Veterinarian Livia Pereira who cared for Ariel recently had said that for unknown reasons, the lion's white blood cells attacked healthy cells due to a degenerative disease affecting the medulla, a portion of the brain stem involved in motor functions.
The 3-year-old, 310-pound lion started limping one day last year after spending hours leaping and chasing balloons. Shortly afterward, Ariel's two hind legs stopped working. Then, after surgery to remove a herniated disc, the lion was unable to move its front legs.
Pereira said Ariel's symptoms were similar to those of multiple sclerosis, Parkinson's disease and Guillain-Barre syndrome, an autoimmune disorder that can cause paralysis.
A team of Israeli veterinary neurologists from the Hebrew University of Jerusalem visited the lion to administer tests they hoped would determine what degenerative disease was involved. Results weren't expected until the end of July.
Borges said Ariel was born in the shelter that she and her husband run in the southern city of Maringa, where they care for sick and abandoned animals.
"He was a perfectly normal and docile lion that slept with me until he was 10 months old," Borges said.