Critics in particular found the novel's coverage of intellectual property compelling and connected the book's fiction to Newitz's prior work in journalism covering science and technology.

In 2144, Jack Chen is a chemist who reverse engineers patented pharmaceuticals to manufacture generic versions which she sells on the black market.

She lives on a submarine in the Arctic Sea, outside of the Free Trade Zone, an economic union which covers the majority of North America.

Jack steals an experimental drug called Zacuity, a "productivity enhancer" which causes the user to experience a pleasurable sensation while working.

Med joins Jack and Threezed at Krish's lab, where they develop a drug called RetCon intended to be a counteractive to the addictive properties of Zacuity.

[1] Newitz's non-fiction coverage at io9 included stories that focused on themes they would later incorporate into Autonomous, such as medical technology and the changing landscape of intellectual property.

According to Newitz, they chose Saskatchewan as the setting for the novel in part because they felt that it was "the kind of place that often gets forgotten" in favor of major metropolitan cities in depictions of the future.

They noted the irony that many science-fiction television programs are filmed in Vancouver but depicted as taking place in the United States or other countries.

[3] Autonomous is set in a 22nd century future Earth which has broadly embraced free market economics on a global scale.

[4] In the book, medicine has advanced to the point where complex drug interventions are capable of solving wide varieties of problems beyond illness, including reversing the effects of aging and improving physical fitness.

The character of Paladin, a newly activated robot who is self-aware but unable to act autonomously, is used to explore the idea of freedom and its relationship to consent.

[4] Paladin states that they do not share the human concept of gender and switches from using male to female pronouns halfway through the book at the urging of Eliasz, who struggles with internalized homophobia.

Robertson wrote that "Newitz’s pared-down style makes Autonomous a lean thriller that pairs a fast-moving cat-and-mouse game with an impassioned ethical argument".

[2] Nisi Shawl of The Seattle Times wrote that Newitz was "both extremely funny and unfussily violent" and generally praised the characters with the exception of Eliasz, who she described as an "affectless cipher".

In a review for Tor.com, Lee Mandelo praised the treatment of Paladin's gender and wrote that "for several nonbinary readers, I suspect it will strike a familiar chord".