Gordon was a practicing therapist from 2004 to 2009, working in North Carolina; Chicago, Illinois (where she moved in 2005); and Brooklyn, New York (where she moved in 2007).

Gordon has been married to actor and Comedian Kumail Nanjiani since 2007. It is her second marriage. She met Nanjiani at a comedy show in Chicago where he was performing; she lightly heckled him, an encounter depicted in The Big Sick. In the ensuing months, they began dating but Gordon fell seriously ill and was put into a medically induced coma before being diagnosed with Still's disease. Gordon recovered and three months later — twelve months after meeting — they married. They previously lived in Chicago and New York, but later moved to Los Angeles.

Gordon has written two webseries aimed at teenagers, called Power Up and ExploreD, at Disney.com. She wrote for the second season of The Carmichael Show on NBC, writing an episode called "New Neighbors". In addition to writing, Gordon also produces comedy. In 2010, she created a weekly live show co-hosted by Jonah Ray and Kumail Nanjiani called The Meltdown with Jonah and Kumail, located in the back of comic bookstore Meltdown Comics; Gordon served as Producer and booker. In 2011 she was asked by Chris Hardwick, who wanted to turn the space into a curated comedy venue, to act as program Director. She served as program Director of the Nerdist Showroom at Meltdown Comics from 2011 to 2012. In 2013 Comedy Central ordered a pilot for The Meltdown with Jonah and Kumail, which was made a series in 2014; Gordon was an executive Producer.

Gordon's first book, Super You: Release Your Inner Superhero, a tongue-in-cheek self-improvement guide, was released in 2015.

Gordon also co-wrote the screenplay of and co-executive produced the 2017 film The Big Sick, with her husband Kumail Nanjiani. The critically acclaimed film is based on the beginning of their relationship, with Nanjiani playing himself, and Gordon (renamed Emily Gardner) played by Zoe Kazan. The Big Sick was directed by Michael Showalter and produced by Judd Apatow.

Gordon and Nanjiani's script won the Independent Spirit Award for Best First Screenplay. It was also nominated for a 2018 Academy Award for Best Original Screenplay, as well as screenwriting awards from the Writers Guild of America, the Gotham Awards, and a dozen critics' associations.

Gordon is signed to adapt Cynthia D’Aprix Sweeney 2016 novel The Nest for Amazon's film studio. Jill Soloway and Andrea Sperling will produce the feature film.