De Niro, Witherspoon for The Intern
The Oscar-winners are both in talks to star in the comedy, reported Deadline.
The pair were apparently hand-picked for the roles by the film's writer and director Nancy Meyers.
Reese, 37, will play the founder of a top fashion website, who is taking part in her company's senior intern scheme.
De Niro, 70, will play the elderly widower assigned to her, who used to be a businessman.
Meyers previously said of the movie: "The character is much younger than me, but I was attracted to the pressures the character feels with her business, her husband and kids, and seeing all this from the point of view of a man who has been through it."