The QI star, 65, was a regular user of the platform but has now deactivated his account.
According to reports, his last tweet was a picture of Scrabble tiles spelling out the word "Goodbye".
Instead of his Twitter profile, the page now says the account does not exist.
In recent days an account in Fry's name has appeared on the social network Mastodon, with a post asking other users how it works.
"Well, I’m slowly getting a little more confident and paddling out deeper into the Mastosphere," says a follow up post.
"Trousers now rolled up to the knees and the water not feeling as cold…"
Several other celebs have already left Twitter since Musk took over towards the end of October.
And Ghost star Whoopi Goldberg recently confirmed that she was quitting.
Speaking on US talk show The View, she said the whole thing felt "messy" and that she was "getting off".
"I’m going to get out, and if it settles down and I feel more comfortable, maybe I’ll come back," she said.
"But as of tonight, I’m done."
Yahoo has contacted representatives for Fry for comment.
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