Murray has illustrated for such clients as The Globe and Mail, New York magazine, CBC and Canadian Business
In 2000, Murray created Chip Zdarsky as a pseudonym and alter ego for his persona as a comic book writer and illustrator, developing his own independent projects, such as Prison Funnies and Monster Cops (which can be read online or in print) as well as collaborating on a variety of projects, including Dark Horse Comics titles Fierce and Rumble Royale. About his alter ego, Murray said "I wanted to have a sad-sack cartoonist persona that lives in his mom's basement, paints figurines for money, has restraining orders against him. And that became a character." He describes the character as "an idiot who doesn't know what I'm doing. I've had no success in my life. No matter what, I'm going to mess things up." Murray initially attempted to keep the identities separate and secret.
From 2008 to 2014, Murray penned and illustrated a weekly advice column for the National Post called "Extremely Bad Advice". He also wrote another column in that paper, Tear Jerk, in which he reviewed films to see if they could actually make him "weep like a baby."
Along with Kagan McLeod, Ben Shannon, and Cameron Stewart, he is a co-founder of the studio The Royal Academy of Illustration and Design, which produced Rumble Royale.
In 2010, he also launched a mock campaign for Mayor of Toronto. He was not an officially registered candidate, launching his satirical "campaign" through social networking platforms after the deadline had passed to register as a candidate in the real campaign.
In June 2013, Image Comics announced that Chip Zdarsky had teamed up with Invincible Iron Man and Hawkeye writer, Matt Fraction, on a new creator-owned series titled Sex Criminals. The first issue was released on September 23, 2013. Sex Criminals was declared number 1 on Time Magazine's list of Top Ten Comics and Graphic Novels of 2013.
In 2014, Murray won a Will Eisner Award for Best New Series for Sex Criminals.
Zdarsky wrote the first series arc of the relaunched Jughead comic for the 2015 New Riverdale relaunch.
On February 15, 2017, it was announced that beginning that June, Zdarsky would be writing a brand new "back-to-basics" Spider-Man series Peter Parker: The Spectacular Spider-Man that would run alongside writer Dan Slott's run on The Amazing Spider-Man.
In 2020, DC Comics announced that Zdarsky would be among the creators of a revived Batman: Black and White anthology series to debut on December 8, 2020.
