Pic also stars Anthony Mackie and Jonathan Levine, who worked with Rogen and Gordon-Levitt on "50/50," is directing.
The story follows three childhood friends who reconnect on Christmas Eve.
Caplan will play Gordon-Levitt's love interest.
Production starts next week in New York.
Caplan was Emmy-nominated for her performance in Showtime drama "Masters of Sex" and co-stars in Sony's "The Interview," which stars Rogen and James Franco and bows this Christmas.
She is repped by WME and Mosaic.
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