The announcement was made to the cat's 2.3 million followers on Instagram.
According to the post, Lil BUB passed away on Dec. 1. BUB had been battling a "persistent and aggressive bone infection."
"Even knowing this, we weren't expecting her to pass so soon or so abruptly without warning. I truly believe that she willingly made the decision to leave her failing body so that our family would not have to make that difficult decision ourselves," owner Mike said on Instagram.
Lil BUB was the runt of a feral litter found in rural Indiana in 2011.
According to the cat's website, she was born with many genetic abnormalities and was a "perma-kitten" with kitten-sized features her whole life.
Over the years, BUB has been the subject of genetic and biological research and helped raised more than $700,000 for animals in need.
"Dearest BUB, I will never forget your generosity, your limitless supply of love, or your uncanny ability to bring so much magic and joy to the world. I am forever honored and humbled that you chose me as your caretaker. Please visit all of us in our dreams," her owner Mike said on Instagram.