Weir began writing science fiction in his twenties and published work on his website for years. He also authored a humour web comic called Casey and Andy 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 called Cheshire Crossing bridging Alice in Wonderland, Peter Pan and The Wizard of Oz. The attention these gained him has been attributed as later helping launch his writing career, following the failure to publish his first novel attempt called Theft of Pride. His first work to gain significant attention was "The Egg", a 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.

Weir lives in Mountain View, California, in a rented two-bedroom apartment. Since he has a fear of flying, he never visited the set of the film adaptation of The Martian in Budapest, where most of the scenes set on Mars were shot at Korda Studios. In 2015, with the help of therapy and medication, he was able to fly to Houston to visit the Johnson Space Center, and to San Diego to attend Comic-Con.

In 2016, Weir released The Principles of Uncertainty collection of short stories on the TAPAS app platform for short fiction.

In 2017 CBS picked up a pilot written by Weir titled Mission Control, following a group of young NASA astronauts and Scientists. In May of the same year, Weir collaborated with webcomic Artist Sarah Andersen to remake Cheshire Crossing for the website Tapastic.