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Palmerston, named for two-time Prime Minister Viscount Palmerston, arrived at the office as a rescue in 2016 and quickly gained fame for catching mice and appearing in photos with visiting diplomats.
The cat previously made headlines for clashes with Larry, the cat charged with catching mice for the prime minister at 10 Downing Street.
The letter, written from the feline's perspective, said Palmerston is retiring to live with a family in the British countryside.
"Although I am ending my formal role here, I will always be an ambassador for the U.K. and the new Foreign, Commonwealth and Development Office," the letter reads.
The Foreign Office praised Palmerston for his service in a Twitter post.
"We'll all miss him paw-fully, but wish him a purr-fect retirement," the tweet reads.