The cat's popularity turned into business - a movie, commercials, toys, endorsements, appearances and clothing, among many ventures.
"Despite care from top professionals, as well as from her loving family, Grumpy encountered complications from a recent urinary tract infection that unfortunately became too tough for her to overcome", the family's statement read.
Grumpy Cat poses on the set as she makes her broadway debut in "Cats" on Broadway at The Neil Simon Theatre on September 30, 2016, in New York City.
Tardar Sauce became an online celebrity in 2012 when photos of her sour-looking facial expression - caused by feline dwarfism - went viral. "She passed away peacefully on the morning of Tuesday, May 14, at home in the arms of her mommy, Tabatha".
No matter the situation, whether she was sitting in an Easter basket, wearing Santa hats or having her photo taken with Marvel Comics legend Stan Lee, Grumpy mostly looked angry or bored.
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"Some days are grumpier than others..."
Her owners said "Grumpy Cat has helped millions of people smile all around the world - even when times were tough". Within 24 hours, a Reddit post that included images of the cat was trending with more than 25,000 upvotes, according to Know Your Meme, a website that tracks viral Internet content.
"Her spirit will continue to live on through her fans everywhere", they added.
Madame Tussauds in San Francisco unveiled a waxwork of her in 2015.
Fans of the popular feline can buy Grumpy Cat merchandise including clothing, pillows, mugs and phone cases.
By the end of her life, Grumpy Cat had found an internet community numbering in the millions, with 2.4 million Instagram followers, 1.5 million Twitter followers and 8.5 million likes on Facebook. However, her owner, Tabatha Bundesen denied that report in an interview with the Huffington Post.