After three years of graduate school, Cohen took a leave of absence and started writing sample TV scripts. In 1992, this landed him a job writing two of the earliest Beavis and Butthead episodes. In 1993, Cohen began working on The Simpsons, writing or co-writing thirteen episodes. Nearly five years later, Cohen would team with Matt Groening to develop Futurama, where he served as Writer or co-writer of seven episodes and executive Producer and head Writer of the series' entire run. Cohen has won four Primetime Emmy Awards: Two for Futurama and two for The Simpsons.

When the FOX prime-time animated shows unionized in 1998, Cohen was forced to use a different name for professional purposes as there was already another member credited as David S. Cohen and the Writers Guild of America does not allow members to use the same name for onscreen credits. Instead of using his full middle name, he chose to use the middle initial "X"—because it sounded "sci-fi-ish"—and has jokingly said that the "X" would make him "the David Cohen people would remember". The "X" does not actually stand for anything, but Cohen included a period "so people don't think it's some mathematical formula: 'David times Cohen' or something".

Cohen co-developed Futurama, along with The Simpsons creator Matt Groening. Cohen served as head Writer, executive Producer, and voice Director of the series. He was also the voice Director of the Futurama video game. After spending a few years researching science fiction, Groening got together with Cohen in 1997 and developed Futurama, an animated series about life in the year 3000. By the time they pitched the series to Fox in April 1998, Groening and Cohen had composed many characters and storylines; Groening claimed they had "gone overboard" in their discussions. Groening described trying to get the show on the air as "by far the worst experience of [his] grown-up life". The show premiered on March 28, 1999.

Cohen told Newsday in August 2009 that the reported 26-episode order means "[i]t will be up to 26. I can't guarantee it will be 26. But I think there's a pretty good chance it'll be exactly 26. Fox has been a little bit cagey about it, even internally. But nobody's too concerned. We're plunging ahead." Two episodes were in the process of being voice-recorded at that time, with an additional "six scripts ... in the works, ranging in scale from 'it's a crazy idea that someone's grandmother thought of' to 'it's all on paper'. ..."The first episode is tentatively titled 'Rebirth' — and in a surprisingly literal fashion, as things turn out". It aired June 24 on Comedy Central.

Comedy Central picked up the show for 26 new half-hour episodes that began airing in mid-2010.

After four years on the air, the series was canceled by Fox. In a situation similar to the animated Family Guy, however, strong DVD sales and very stable ratings on Adult Swim brought Futurama back to life. When Comedy Central began negotiating for the rights to air Futurama reruns, Fox suggested that there was a possibility of also creating new episodes. When Comedy Central committed to sixteen new episodes, it was decided that four straight-to-DVD films—Bender's Big Score (2007), The Beast with a Billion Backs (2008), Bender's Game (2008) and Into the Wild Green Yonder (2009)—would be produced. Since no new Futurama projects were in production, the movie Into the Wild Green Yonder was designed to stand as the Futurama series finale. However, Groening had expressed a Desire to continue the Futurama franchise in some form, including as a theatrical film. In an interview with CNN, Groening said that "we have a great relationship with Comedy Central and we would love to do more episodes for them, but I don't know... We're having discussions and there is some enthusiasm but I can't tell if it's just me."

Cohen has also been credited with inventing the word "cromulent", meaning "valid" or "acceptable" in The Simpsons episode "Lisa the Iconoclast". Since that time the word was included in Webster’s New Millennium Dictionary. The meaning of cromulent is inferred only from its usage, which indicates that it is a positive attribute. Webster's Dictionary defines it as meaning "fine" or "acceptable".