She has since occasionally returned to SNL as a guest portraying Senator Amy Klobuchar. Other television credits include The King of Queens, Monk, and 30 Rock. She has also played the recurring role of Wanda Jo Oliver on Last Week Tonight with John Oliver.

She appeared in films including Down With Love (2003), Click (2006), I Now Pronounce You Chuck and Larry (2007), My Life in Ruins (2009), Just Go with It (2011), That's My Boy (2012), Sisters (2015), and starred in Wine Country (2019) and A Clusterfünke Christmas (2021).

In 2022, Dratch made her Broadway stage debut in POTUS: Or, Behind Every Great Dumbass Are Seven Women Trying to Keep Him Alive for which she earned a Tony Award for Best Featured Actress in a Play nomination. In 2012 she published her autobiographical book Girl Walks Into a Bar...: Comedy Calamities, Dating Disasters, and a Midlife Miracle.