The 64-year-old will play Alphonse, father of Dr. Frankenstein (David Anders), according to TVLine.
Itzin will first appear in episode 12 of Once's second season, which will also feature Last Resort actor Chad Michael Collins as Frankenstein's brother Gerhardt.
In addition to his 24 role as traitorous US President Charles Logan, Itzin has also appeared on The Mentalist, Covert Affairs and Big Love.
Once Upon a Time aired its 2012 mid-season finale on December 2 on ABC and will return with new episodes on January 6.
Series co-creator Edward Kitsis recently suggested that fictional characters such as Robin Hood and Tarzan could "absolutely" appear on Once, while Mary Poppins was also "in-bounds".
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Watch a promo for the return of Once Upon a Time below: