The comedy-drama, a remake of the British original, stars William H. Macy as unemployed alcoholic Frank Gallagher.
TV Squad reports that Webb will play Frank's estranged ex-wife in an episode later this season.
A similar character, Monica Gallagher, is played by Annabelle Apsion in the original version of Shameless.
Webb is best known for her role as Nancy Spungen in 1986 film biopic Sid and Nancy. Her recent television credits include roles in CSI, Two and a Half Men and House.
Shameless airs on Sundays at 10pm on Showtime.