Morrison's first published works were Gideon Stargrave strips for Near Myths in 1978. Through the early and mid-80s, Morrison continued creating strips and writing for comics while playing in his band The Mixers. In 1985, he began writing for Marvel UK.

In 1987, he and Steve Yeowell created Zenith, one of the earliest examples of deconstructing the superhero genre. His work on Zenith got the attention of DC Comics, which accepted his proposal for Animal Man. He subsequently worked on comics and graphic novels as Doom Patrol , Legends of the Dark Knight and Arkham Asylum: A Serious House on Serious Earth. In 1989, he stirred up controversy for writing The New Adventures of Hiltler, which used Adolf Hitler as its lead character.

In the 90s, Morrison continued working for DC and for its imprint Vertigo through which he published Sebastian O, The Mystery Play and Flex Mentallo. It is with Vertigo that he published what is arguably his most ambitious work, The Invisibles.

In the 2000s, Morrison has done as much work for Marvel as DC for which he wrote the New X-Men. In 2005, he started a 12-issue story arc called All Star Superman, which was awarded with two Eisner Awards and several UK Eagle Awards.

He is one of the four contributing writers, along with Greg Rucka, Geoff Johns and Mark Waid, to DC's 52 week series 52.

In addition to his comic book work, Morrison is also a successful playwright and has written two plays performed by Oxygen House at the Edinburgh Fringe.