Her most recent veterinary check found that she was suffering from a worsening condition, according to the Animal Adventure Park in New York.
Millions of viewers worldwide watched a live stream in 2017 of April giving birth to a calf boy named Tajiri.
Fans of the giraffe tuned in over a seven-week period between February to April in 2017, hoping to catch the birth.
Reacting to the news, one Twitter user said: “I remember this!! I watched the birth and I kept checking on her baby watching it grow too.
“Giraffes are so amazing. She was special. I know she stole a lot of hearts including mine.”
Last summer veterinary imaging showed that April had arthritis in her feet and problems in her left hind leg.
In a Facebook post, the Animal Adventure Park said: “We credit and thank the outstanding collective care provided by the park’s veterinarians and animal care team with keeping April happy and healthy during her more than five year stay at Animal Adventure.
“Both teams have made every possible effort to keep her comfortable and prolong her life while managing her condition.
“Over the past year, accommodations were made and treatments performed, including yard substrate changes, installation of a state-of-the-art padded barn flooring system, coupled with farrier work, dietary and medical changes.
“April’s most recent veterinary exam identified the acceleration of April’s condition, prompting the determination that euthanasia was the humane and appropriate course of action.”