He authored a humor web comic, Casey and Andy,[NB 1] featuring fictionalized "mad scientist" versions of himself and his friends (such as writer Jennifer Brozek) from 2001 to 2008.

He also briefly worked on another comic, Cheshire Crossing (bridging Alice in Wonderland, Peter Pan, The Wizard of Oz, and Mary Poppins), from 2006 to 2008.

[9] His first work to gain significant attention was "The Egg", a 2009 short story that has been adapted into a number of YouTube videos, a one-act play, and is the overarching concept of Everybody, the third album by American rapper Logic.

[1][10] Weir wrote his first published novel, The Martian, to be as scientifically accurate as possible, doing extensive research into orbital mechanics, conditions on the planet Mars, the history of human spaceflight, and botany.

"[14] A fan-fiction story written by Weir, "Lacero", was published in the 2016 edition of Ready Player One, making it canonical to the book's fictional universe.

[16] After announcing that the Zhek project had been "back-burnered", Weir moved on to another hard sci-fi novel, Artemis, with a female protagonist, set on the Moon in the 2080s–2090s.

[19] In 2017, CBS picked up a pilot written by Weir titled Mission Control, following a group of young NASA astronauts and scientists.

[20] In May of that year, Weir collaborated with webcomic artist Sarah Andersen to reillustrate Cheshire Crossing for Tapas, before publishing it as a stand-alone graphic novel in July 2019.

[21] In November 2019, a film adaptation of Cheshire Crossing was announced from Amblin Partners and Walt Disney Pictures, to be produced by Michael De Luca and written by Erin Cressida Wilson.