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. Originally published as a free serial on his website, some readers requested he make it available on Amazon Kindle. First sold for 99 cents, the novel made it to the Kindle bestsellers list. Weir was then approached by a literary agent and sold the rights to Crown Publishing Group. The print version (slightly edited from the original) debuted at No. 12 on The New York Times bestseller list in 2014. The Wall Street Journal called it "the best pure sci-fi novel in years". It was adapted into a film starring Matt Damon and Jessica Chastain, which was released in 2015.

In 2015 Weir announced he was working on his second novel, provisionally titled Zhek, which he described as "a more traditional sci-fi novel with aliens, telepathy, faster-than-light travel, etc." 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. The work functions as a prequel to the main novel. Also in 2016, Weir released The Principles of Uncertainty, a collection of short stories, on the website/app Tapas.

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. The thriller, published in 2017, follows Jazz, a 26-year-old woman constrained by her small town (which is also the only city on the Moon). On September 26, 2017, it was announced that Phil Lord and Christopher Miller had been hired to develop and direct a film based on the novel.

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