[6] He became known early in his career for his creator-owned work on The Five Fists of Science and Casanova, before taking on a number of assignments for Marvel Comics.

He and illustrator Christian Ward created the ODY-C series in 2014, a science-fiction retelling of the Odyssey with the characters' genders changed to female.

Also in 2015, Fraction and Kelly Sue DeConnick's company, Milkfed Criminal Masterminds, signed a two-year deal with Universal Television to adapt some of their comic books, as well as original TV series concepts.

[23] [needs update] In 2018, Milkfed Criminal Masterminds signed another two-year overall deal, this time with Legendary TV to adapt several of their creator-owned comics, as well as produce exclusive, original projects developed by the duo for television across traditional and non-traditional platforms.

[24] [needs update] In 2019, Fraction and Elsa Charretier co-created the graphic novella crime series, November, for Image Comics.

In 2020, Sex Criminals concluded with issue #69, volumes 2 and 3 of November were released, and Adventureman, the long-anticipated series from Fraction and Terry Dodson and Rachel Dodson began releasing from Image Comics, and his and Lieber's run on Superman's Pal, Jimmy Olsen concluded, with a collected trade paperback entitled Who Killed Jimmy Olsen?

He also planned to make a cameo appearance as a member of the Tracksuit Mafia, but was unable to commit to this, due to complications stemming from the COVID-19 pandemic.

Fraction is married to Kelly Sue DeConnick, a comic book writer and adapter of manga into English,[3][29] whom he met when they were both participants on the Warren Ellis Forum.