Because Mark is left entirely alone on the planet, one of the novel's core themes is the effect of isolation on the individual. Mark is forced to depend only on himself to fight elements of the planet as well as to make sure he's able to have enough food to survive. He has no one to talk to and limited forms of entertainment, allowing the reader to see what impact his extreme isolation has on him. Life is hard on Mars, so Mark has to struggle to stay alive. His daily routine quickly becomes mundane and lacking in any joy, serving as a reminder that humans need to interact with others and that in the absence of this social connection, people can be left feeling isolated and empty.

The novel's setting on Mars allows Weir to add a new element to the traditional theme of man versus nature. Every day brings a new battle against nature for Watney. Because he's on Mars, he has to go through several steps and put on many layers of protective gear just to walk outside. Mars's dry climate creates its own problems, as dust storms can destroy equipment and threaten his survival. In order to survive, Watney must learn to navigate life in this harsh and alien world.

Because Watney is a scientist, the novel also focuses on science and the human ability to fight for survival. Weir takes the time to explain the botany, chemistry, math, and engineering knowledge Watney must utilize to survive life on Mars. Watney's scientific spirit also shows us that with each hurdle, he refuses to give up and continues to use his knowledge to find clever ways to stay alive.

Friendship is another key theme in the text. Once the crew realizes that Watney is not dead, they vote to return to Mars, even though it will greatly extend their mission. They accept the possible danger they're putting themselves in, because they believe that retrieving their crew member and friend is the right thing to do.