The two stars will team up for "The Comedian" next year with the producers behind 46-year-old Aniston's 2014 movie "Cake", reported Sun online.
In the film, De Niro, 72, will play an insult comic, who falls for Aniston's character at a wedding.
It's not the first time De Niro has tackled stand-up comedy onscreen - he played obsessed fan Rupert Pupkin opposite Jerry Lewis in 1982's "The King of Comedy".
Reports suggest the actor has been trying to make the film for years.
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