In 2008, Chalke became the spokesperson for a line of women's underwear by Hanes that included a series of commercials directed by her Scrubs co-star Zach Braff.

In early 2011, she starred in the CBS television series Mad Love, a romantic comedy which debuted as a midseason replacement and was cancelled after only one season was produced.

[9][10] Chalke was signed by former Scrubs executive producer Bill Lawrence to play the love interest of Bobby Cobb in the series Cougar Town.

[11] Chalke starred in the ABC comedy series How to Live with Your Parents (For the Rest of Your Life), which premiered April 3, 2013, and which was cancelled one month later.

She played Polly, a single and very uptight divorced mother who found herself moving back in with her parents (Elizabeth Perkins and Brad Garrett) because of the economic downturn.

Also in 2013, she played a frantic mother named Casey Hedges in the Grey's Anatomy season 9 episode "Can't Fight This Feeling".

[12] On May 16, 2017, it was confirmed that eight episodes of the show were greenlit by ABC and would air mid-season in 2018 with Chalke returning, but playing a role other than Becky Conner.

In February 2021, Chalke co-starred alongside Katherine Heigl in the role of Kate Mularkey for the Netflix series Firefly Lane.