The former Mad Love actress will play Bridget, the estranged wife of Ashton Kutcher's character Walden Schmidt.
Bridget is divorcing Schmidt, according to TV Guide, and the publication also reports that she will appear in several episodes of the CBS comedy in a recurring role.
Greer previously made a brief guest appearance on the show as Myra - a love interest for Charlie Sheen's character Charlie Harper - in 2007.
She also spent two years playing Kitty Sanchez on Arrested Development and has made guest appearances on How I Met Your Mother, The Big Bang Theory and Modern Family.
Two and a Half Men's ninth season will premiere on September 19 on CBS.
Watch a short clip of Ashton Kutcher's recent appearance on The Late Show with David Letterman below: