Smith was first named as one of a number of actresses being considered for the FX series last week.
The Saw star will play the ex-wife of Sheen's Charlie, a former baseball player turned anger therapist, according to Deadline.
She is believed to have beaten out Dexter's Julie Benz, Work It's Kate Reinders and In Plain Sight's Nichole Hiltz for the role.
A second female lead, to play Charlie's own therapist, has yet to be cast. Hellboy's Selma Blair and 90210's Elaine Hendrix are both rumoured to be up for the part.
Showrunner Bruce Helford recently described Anger Management as a "smarter" comedy, calling Charlie Sheen "a strong actor".
"[Charlie] hasn't had an opportunity to tap into that in a while," he said in October. "But he is capable of playing much more complicated characters."
The series has been picked up for an initial ten-episode run and will premiere on FX in June.
> Charlie Sheen: 'New sitcom is playground for the imagination'