The 59-year-old will play the mother of TGS (30 Rock's show-within-a-show) writer Frank Rossitano, confirms Entertainment Weekly.
LuPone last appeared on screen as Marc St. James's mother in Ugly Betty. Her TV credits include Oz, Frasier and Law & Order.
She won a Tony Award in 1979 for originating the role of Eva Peron in the Broadway production of Evita. Musicals The Cradle Will Rock, Les Misérables and Sunset Boulevard are also on her resumé.