The 7-year-old red panda named Shama died over the weekend.
"Shama's death is a big loss for all of us and for those who study and care for red pandas everywhere," said National Zoo Director Dennis Kelly.
She became well known at the zoo as the mate of Rusty, who escaped the National Zoo last year. Shama gave birth to three cubs earlier this summer but developed a brain disorder that "quickly progressed."
"Shama was euthanized due to her worsening clinical condition and poor neurological function, which was likely attributed to accumulation of fluid in the brain," the Zoo said in a statement Monday.
Shama, Rusty and the cubs were housed at the Smithsonian Conservation Biology Institute in Front Royal.
Zookeepers say Shama's three cubs are now being hand-reared by animal keepers. The cubs are active, but one is smaller than the others and is being treated for pneumonia.