The show will be Aniston's first regular series role since "Friends" ended in 2004, and Witherspoon's first ever in an ongoing show.
The show doesn't have a name or a proposed air date (though spring of 2019 is a decent bet).
Separately, Apple also confirmed widely reported plans to revive Steven Spielberg's Amazing Stories, a 1980s NBC anthology series, with Spielberg and Bryan Fuller (American Gods) as producers.
Few details are known about the series other than its big stars and its concept, which is built around a morning TV show in the style of "Today" and "Good Morning America".
The Hollywood Reporter reports that the deal is for a straight-to-series, two-season order of 20 episodes for the untitled drama.
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Apple hasn't said where people will be able to watch its shows, though the company hopes to release its first slate in 2019, Bloomberg reported in October. Aniston and Witherspoon will star, executive produce and co-own the show alongside Michael Ellenberg's Media Res company, which produces the show for Apple.
Stetler will serve as the show's consultant and House of Cards writer Jay Carson will executive produce as well as pen the series.
Since leaving his position as head of drama at HBO, Ellenberg has focused on development and has teamed with Bron Studios to launch Media Res.
The news is thrilling for fans of the two talented women. It's unclear if Apple will make the shows available by iTunes or another platform, and whether access will be based on a subscription or advertising-based model.
Both actresses were nominated for an Emmy in the Outstanding Lead Actress in a Limited Series or Movie category, which Kidman took home.