Her first experimenting with writing for TV was at age 13, when she took a stab at writing an episode of M*A*S*H. She attended college at UC Berkeley, studying linguistics as an undergrad and graduate student. While in grad school, she submitted spec episodes to Star Trek: The Next Generation.
After winning a spot in the Walt Disney writers' fellowship (1992–93), Espenson worked in sitcoms for a number of years. She is also a Star Trek alumnus, having written the Deep Space Nine season 4 episode "Accession".
Espenson joined Buffy the Vampire Slayer as a writer during season three, her first episode being "Band Candy". She also served as an executive story editor during that season. From season 4 onwards she became one of the most prolific writers, writing between four and six episodes each season, often tending towards the humorous aspects of the Buffyverse, but also doing very serious episodes like "After Life". She co-wrote the Hugo Award-winning episode "Conversations with Dead People" as well as the penultimate episode "End of Days" (the only episode written by Espenson that featured Faith, Eliza Dushku's character), totaling 23 writing credits on Buffy with only Joss Whedon and Marti Noxon having written more episodes. From season four onwards Espenson also served as a producer on Buffy, being a co-producer during the fourth, a producer during the fifth, a supervising producer during the sixth and a co-executive producer during the seventh season.
After having production credit on Tru Calling (starring Eliza Dushku), The Inside (co-created and executive-produced by Tim Minear), Jake in Progress and Gilmore Girls (while also writing episodes for all of these as well as for The O.C. and Eureka), Espenson wrote two season three episodes of the re-imagined Battlestar Galactica series (starring Tahmoh Penikett). She joined the staff in season 4, writing two more episodes and earning a co-executive producer credit. She also wrote The Plan.
Espenson joined Dollhouse in October 2008, around the time Steven DeKnight left his consulting duties. According to Joss Whedon, "young Steve DeKnight, after writing and shooting an ep so cool it helped not only define the show but save its ass, is ending his consulting duties, the f#%&er. I will be crying on the shoulder of Jane Espenson come Monday, so congratudolences are in order. Excited for the Jane Flava." In her first interview after joining the staff she applauded the show: "I think it's extremely good, and the concept just blows me away: It's fantastic, this notion of people who have been erased and are now imprintable with whatever you want them to be. ... It's sci-fi of the most human kind. It's sci-fi about people, as opposed to, you know, phenomena. And I really love that."
Espenson wrote or co-wrote two Dollhouse scripts, episode ten, "Haunted", with Maurissa Tancharoen and Jed Whedon, and episode eleven, "Briar Rose". This makes her the only person besides Joss Whedon that has written for all four Joss Whedon-shows.
Espenson will be co-executive producer and eventually show-runner on the Battlestar Galactica-prequel Caprica.