Grumpy Cat's owner Tabatha Bundesen posted the sad news to Twitter on Friday morning.
"Grumpy encountered complications from a recent urinary tract infection that unfortunately became too tough for her to overcome."
"Besides being our baby, and a cherished member of the family, Grumpy Cat has helped millions of people smile all around the world, even when times were tough."
Grumpy Cat's real name was Tardar Sauce.
Grumpy Cat's breed has never been confirmed but her owners put her small size and perpetual scowl to "feline dwarfism."
Grumpy Cat's fame lead to lucrative deals with companies such as Nestle Purina petcare and coffee company Grumpy Beverage.
Media reports have estimated Grumpy Cat's net worth as anything from $1m to $100m.