The actor, 52, was asked about Trump's bid for the White House while doing press for his latest film, "Alice Through the Looking Glass".
Depp returns as the Mad Hatter in the sequel to the 2010 film.
"Here's the thing - if Donald Trump is elected President of the United States, in a kind of historical way it's exciting because we will see the actual last President of the United States," Depp said.
"It just won't work after that."
The actor previously portrayed the billionaire businessman in an hourlong fake show for the comedy website Funny or Die in February. The faux film poked fun at Trump's best-seller The Art of the Deal.
Funny or Die's Art of the Deal featured an all-star cast, which included Alfred Molina, Robert Morse, Patton Oswalt, Jacob Tremblay, Jack McBrayer, Michaela Watkins, Henry Winkler, Stephen Merchant and Christopher Lloyd, among others.
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