Cusack will appear in all 12 episodes of the show as Sheila, an agoraphobic Chicago housewife with a sexually active teenage daughter who strikes up a special friendship with William H. Macy's character, Frank Gallagher, the cable network said.
Production on the first season is to begin in mid-September, with the series set to premiere Jan. 9.
Cusack has twice been nominated for an Oscar for Best Supporting Actress for her roles in "Working Girl" and "In & Out." Her other film credits include "Sixteen Candles," "Say Anything…," "Class," "High Fidelity," "Cradle Will Rock" and "Grosse Pointe Blank."
"Shameless" is based on the long-running hit U.K. series about Gallagher, a "far-from-stellar working-class patriarch of an unconventional Chicago brood of six motley kids whose eldest daughter keeps the home afloat while he's out drinking and carousing," Showtime said in a synopsis. Gallagher's daughter is to be played by Emmy Rossum.