The actress is to play a non-profit attorney whose mysterious fate leads her to Eli in a Season 2 episode of the show called "Grace," the network said.
Jonny Lee Miller plays Eli Stone.
The guest gig reunites Holmes with "Stone" co-creator and executive producer, Greg Berlanti, whom she previously worked with on "Dawson's Creek."
Holmes recently starred in the feature film, "Mad Money." Her other big-screen credits include "Thank You for Smoking," "Wonder Boys," "The Ice Storm" and "Batman Begins."