Her first three comedy albums released are Self Help (2006), Hail to the Freaks (2011) and I'm Gonna Die Alone (And I Feel Fine) (2016), the latter also serving as her debut stand-up feature for Netflix.

Her debut book, I Can Barely Take Care of Myself: Tales From a Happy Life Without Kids, was published in April 2013, and became a New York Times bestseller.

[5] Kirkman performs stand-up comedy in Los Angeles, California, appearing regularly at the Hollywood Improv, The Laugh Factory, Largo and The Upright Citizens Brigade Theatre.

On June 3, 2010, she announced she would be leaving Chelsea Lately to join the writing staff for Perfect Couples, a romantic situation comedy which premiered as a mid-season replacement on NBC on January 20, 2011.

[14] Perfect Couples was removed from the NBC schedule on March 11, 2011, and Kirkman returned to the writing staff of Chelsea Lately in April 2011.

In November 2013, Deadline reported that FX had landed a script deal to Jen, a half-hour sitcom executive produced, written by and starring Kirkman.

The project was backed by Borderline Amazing Productions, with executive producers Chelsea Handler, Tom Brunelle and Brad Wollack.

[17] In 2017 and 2018, Kirkman contributed to the first two seasons of The Marvelous Mrs. Maisel as a writer, consultant, and producer, providing many of the jokes for the main character's stand-up routines.

"[18] On October 11, 2017, it was reported that ABC had started development on The Mighty Quinn, a television series written by Kirkman and produced by Julie Anne Robinson.

The website featured interviews with comedians such as Joy Behar, Margaret Cho, Sue Murphy, Amy Poehler and Sarah Silverman.

Kirkman has cited Joan Rivers, Howard Stern, Roseanne Barr, Dave Chappelle, Chris Rock and David Spade as having an influence on her sense of humor.