She had a five-year stint as a writer and producer on Buffy the Vampire Slayer and shared a Hugo Award with Drew Goddard for her writing on the episode "Conversations with Dead People".

In 2010, she wrote an episode of HBO's Game of Thrones, eventually earning a Writers' Guild Award for her involvement with the show.

She has written numerous comic books, edited multiple volumes of essays, and published several short stories.

[4] Lakoff also mentioned her year-long work on the "metaphorical structure of causation" in the acknowledgments section of Philosophy in the Flesh: The Embodied Mind and Its Challenge to Western Thought (1999, ISBN 0-465-05674-1).

[2] In 1992, Espenson won a spot in the Disney Writing Fellowship,[1] which led to work on a number of sitcoms, including ABC's comedy Dinosaurs and Touchstone Television's short-lived Monty.

[1] After years in sitcoms, Espenson decided to switch from comedic to dramatic writing and submitted her sample scripts to Buffy the Vampire Slayer.

[5] In 1998, Espenson joined Mutant Enemy Productions as executive story editor for the third season of Buffy the Vampire Slayer.

Espenson and Drew Goddard co-wrote the seventh-season episode "Conversations with Dead People," for which they won the Hugo Award for Best Short Dramatic Presentation in 2003.

[7] As one of BSG's co-executive producers, she worked on every fourth-season episode starting with "He That Believeth in Me"; she was also the writer of "Escape Velocity" and "The Hub" and co-wrote The Face of the Enemy webisodes.

[9] In January 2009 it was announced that she had joined the spin-off series Caprica as co-executive producer and would take on showrunner duties midway through the first season.

The series also generated Husbands, a hardback comic-book collection of stories rendered in a variety of different drawing styles, from Dark Horse Comics.

She has worked on Angel, Tru Calling, The Inside, The Batman, Andy Barker, P.I., Jake in Progress and Dollhouse, and was the co-creator of Warehouse 13.

She edited the follow-up collection Serenity Found: More Unauthorized Essays on Joss Whedon's Firefly Universe (BenBella Books, 2007, ISBN 9781933771212) She is the editor of Inside Joss' Dollhouse: From Alpha to Rossum (BenBella Books, 2010, ISBN 9781935251989), a similar collection of essays about Dollhouse.

Her short story, "Nobel Prize Speech Draft of Paul Winterhoeven, With Personal Notes", was published in the September 2021 issue of Future Science Fiction Digest.

[25] In 2016, Espenson served on the MoPOP (Museum of Pop Culture, Seattle) committee to select inductees into the Science Fiction and Fantasy Hall of Fame.

Espenson has written for three of the 101 Best Television Series as determined by the Writers Guild of America: Battlestar Galactica, Game of Thrones and Buffy the Vampire Slayer.

[27] Espenson has appeared as an "expert witness" on the Judge John Hodgman podcast episodes "Science Friction"[28] and "Vampirical Evidence.