Ferguson, 51, made the announcement to his studio audience Monday.
"CBS and I are not getting divorced, we are 'consciously uncoupling,' but we will still spend holidays together and share custody of the fake horse and robot skeleton, both of whom we love very much," he said in a statement.
It's the second late-night retirement for CBS, with David Letterman's decision to leave "Late Show" in 2015. Letterman will be succeeded by Stephen Colbert.
Ferguson says he will retire this December. CBS did not announce who will replace him.
The Scottish-born actor-comedian began as host of "The Late Late Show" in 2005. He is also known for playing Nigel Wick on "The Drew Carey Show," portraying a pothead gardener in the 2000 movie "Saving Grace," and voicing characters in the animated movies "Brave" and "How to Train Your Dragon."
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