Dratch's breakthrough role was her tenure as a cast member on the NBC sketch comedy series Saturday Night Live from 1999 to 2006.

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.

[10] Dratch has appeared in several films, including Martin & Orloff, The Hebrew Hammer, Down with Love, Dickie Roberts: Former Child Star, Click, I Now Pronounce You Chuck and Larry, Spring Breakdown, and My Life in Ruins.

Dratch also made television appearances on NBC's Third Watch and in a recurring role on The King of Queens (playing Denise, the on-off girlfriend of Spence, who worked in a bowling alley).

Other television appearances include Portlandia, Monk, Frasier, Wizards of Waverly Place, 30 Rock, Aqua Teen Hunger Force, Inside Amy Schumer, Ugly Betty, and more recently, in season five of The Middle.

She went on to play a variety of small guest roles in several episodes of the first season, including Barbara Walters, Elizabeth Taylor, a cat trainer, a custodian, a blue monster, and a doctor.

[12] On March 19, 2012, Dratch's memoir, Girl Walks into a Bar...: Comedy Calamities, Dating Disasters, and a Midlife Miracle was published.

Dratch's recurring characters included Denise, a Boston teen; Sheldon, the junior-high-school boy from Wake up, Wakefield; one of the Luvahs (with Will Ferrell, as two pretentious professors); Abe Scheinwald, a Hollywood producer with a terrible acquisition record; and, perhaps most memorably, Debbie Downer, a depressed woman who brought others' moods down while saying grim non sequiturs.

[14] In December 2011, she made a guest appearance on Saturday Night Live's Christmas show, hosted by former cast member Jimmy Fallon.

[15] On September 29, 2018, she appeared as Senator Amy Klobuchar in the opening sketch, about the confirmation hearings of Supreme Court nominee Brett Kavanaugh.