She has worked on several television series and comic books, as well as on a variety of other projects.
She is perhaps best known for her five-year stint (from 1998 to 2003) as a writer and producer on Buffy the Vampire Slayer. Espenson wrote or co-wrote twenty-three episodes, beginning with the third-season episode "Band Candy" and ending with Buffy's penultimate episode, "End of Days". She is perhaps best known for the humorous episodes that she has penned, including "Triangle" and "Intervention", but she has also written entirely serious episodes such as "After Life".
Along with Drew Goddard, Espenson co-wrote the seventh-season episode "Conversations with Dead People", for which she won the 2003 Hugo Award for Best Short Dramatic Presentation.
Espenson's other television projects include episodes of Star Trek: Deep Space Nine, Gilmore Girls, The Inside, and two episodes of Angel and one of Firefly, with another finished but unproduced as of the cancellation of that series.
Espenson is also the editor of Finding Serenity: Anti-Heroes, Lost Shepherds and Space Hookers in Joss Whedon's Firefly (BenBella Books, 2005), a collection of non-fiction essays on the short-lived television show Firefly.