The duo will appear in an episode of the show in January, The Hollywood Reporter says.
Vardalos will play Karen Winterbottom, while Gilpin will appear in the show as Karen's sister Marcy.
Vardalos previously starred in My Big Fat Greek Wedding and has had guest roles in shows such as Drop Dead Diva, The Good Guys and Cougar Town.
Meanwhile, Gilpin has appeared in shows including Frasier and Make It or Break It.
Grey's Anatomy will return with new episodes next year in the US. The season continues in the UK on Wednesdays at 10pm on Sky Living.
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