Veterinarians at the Clearwater Marine Aquarium announced Winter the dolphin died Thursday night.
The prosthetic-tailed dolphin has been fighting a gastrointestinal infection.
"During preparation for a procedure, the CMA Animal Care team observed that Winter’s behavior and vital signs were declining," the aquarium said in a statement. "The medical team tried several life-saving efforts, but she died being held by her caregivers."
Winter was rescued off the coast of Florida in 2005 after she became entangled in a crab trap and lost her tail. Her story became the subject of the book and movies, "Dolphin Tale," which Winter stared in.
The aquarium announced it will be closed Friday to give the staff time to grieve.
The aquarium said it will announce plans for a memorial in the near future.