The following version of this book was used to create this study guide: Weir, Andy. Project Hail Mary. New York: Ballantine Books, 2021.

When the novel begins, Ryland Grace, a junior high school science teacher, awakens on a spaceship called the Hail Mary with no memory of who he is or why he is there. Also in the dormitory of the ship are the dead bodies of his crewmates, astronauts Commander Yáo Li-Jie and Olesya Ilyukhina. As he begins to explore the ship, two memories help him orient himself. In one, he sees an email about a red line that has been observed by astronomers in the solar system. In another, a friend tells him that this line, called the Petrova line after its discoverer, is going to cause the sun to become dimmer over the next several years, to the extent that there might be an ice age. Ryland realizes it must be his job to solve this problem.

In another flashback, Ryland is visited in his classroom by a woman named Eva Stratt. She tells him she is a member of the European Space Agency tasked with solving the Petrova line problem and that she wants Ryland to examine an alien life form that was brought back from space by a mission called Arclight. She chose Ryland because he once wrote a controversial paper arguing that life does not require water. This paper caused Ryland to lose his job at the university where he worked prior to becoming a junior high teacher. Ryland goes to Stratt's lab and examines the life form, which they call Astrophage because it “exists on a diet of stars” (52). He seeks to determine why the Astrophage, which seem to possess high quantities of energy, go to Venus. Their flight path to Venus causes the Petrova line that is dimming the sun.

In the present, Ryland explores the Hail Mary and discovers there are 20,000 kilograms of Astrophage on board. He also finds the ship's container vessels, called beetles, and determines that they are meant to send information back to Earth. He realizes that this means that he is not meant to return to Earth and he will die in space. In a flashback, Ryland becomes determined to solve the Astrophage problem so his students do not have to live through a terrible disaster. He discovers that Astrophage go to Venus seeking carbon dioxide, which they need to breed. When he calls Stratt to tell her this, he is immediately picked up by U.S. Air Force personnel and taken to a Chinese aircraft carrier in the middle of the ocean. There, he has a meeting with Stratt and scientists and heads of state from around the world. They are all working on a mission to save the world, which they call Project Hail Mary, and Ryland is now a member. They explain that they are going to make an Astrophage-powered spaceship and send astronauts to a star in another galaxy called Tau Ceti, which is not affected by Astrophage. This is where Ryland is in the present-day timeline.

In another flashback, Stratt tells Ryland she is trying to decide if the astronauts should be put into comas on the journey to Tau Ceti to avoid potential conflict and emotional side effects of a long space odyssey. She notes that a Thai research group discovered that some people possess a gene that makes them resistant to the potentially negative side effects of a coma, including death. Ryland suggests that they choose astronauts for the space mission who have the coma-resistance gene. In the present, Ryland sees another ship, clearly not from Earth, outside the Hail Mary. He calls it the Blip-A because of the way it appears on the Hail Mary's radar. He thrusts the ship's engines three times and the Blip-A does the same. Then a pair of robot arms attached to the Blip-A tosses a cylindrical object in his direction. He dons the ship's extravehicular activity (EVA) suit and goes outside to catch it.

In a flashback, Ryland and Stratt meet a scientist named Dr. Lokken, who Stratt strong-arms into designing lab equipment for the Hail Mary. In the present, Ryland opens the cylinder and finds a model that is meant to show him where the alien on the Blip-A is from, a system that Earth scientists call 40 Eridani, and that this system is also affected by Astrophage. The alien in the Blip-A connects his ship to the Hail Mary with a tunnel. Ryland enters the tunnel and sees the alien, which looks like “a big-assed spider” (174). There is a wall down the center of the tunnel so that Ryland can breathe oxygen on one side and the alien, who Ryland calls Rocky for his craggy appearance, can breathe ammonia on the other side. Rocky's home planet, which Ryland calls Erid, has an atmosphere made of ammonia. Rocky's speech sounds musical to Ryland, and he decides to use sound-wave analysis software to try to translate what he is saying. This is effective, and Ryland and Rocky discuss their mutual Astrophage problem.

In a flashback, Stratt and Ryland visit an energy scientist, Dr. Redell, who is in a New Zealand prison for embezzlement. Redell says that it would be possible to enrich massive quantities of Astrophage to fuel the Hail Mary by covering the Sahara Desert with black panels that will absorb sunlight. Redell joins Project Hail Mary. In the present, Rocky tells Ryland that all of his crewmates got sick and died. In a flashback, Stratt asks a climatologist named Dr. Leclerc to figure out how to forestall an ice age by releasing a large amount of greenhouse gas into Earth's atmosphere. They accomplish this by blowing up glaciers on Antarctica with fusion bombs. Ryland is tested for the coma-resistance gene. In the present, Rocky makes a bubble full of ammonia he can move around in so he can enter the Hail Mary.

Rocky tells Ryland that he will give him enough Astrophage fuel to allow him to return to Earth. In a flashback, Ryland meets the astronauts chosen for the space mission, including the science specialists, Annie Shapiro and Martin DuBois, whom he will train. DuBois mentions that Ryland has the coma-resistance gene. In the present, Ryland and Rocky decide to collect a sample from the atmosphere of a planet near Tau Ceti, which they call Adrian. Ryland must leave the ship to collect the sample, a dangerous mission that he fulfills courageously. But as they try to fly out of Adrian's atmosphere, they discover a hole has been burnt into the Hail Mary's hull. This causes the ship's gravity to increase rapidly. Ryland is tossed around the control room and pinned down by a chair. Rocky leaves the safety of his bubble and pulls the chair off Ryland, then collapses. Ryland manages to pull Rocky to the safety of his ammonia-filled airlock before passing out as well. A day passes and Ryland recovers, but Rocky continues to lie motionless in the airlock. Finally, Rocky awakens.

In a flashback, Ryland is living in a trailer near the Baikonur launch facility days before the Hail Mary's launch. An explosion occurs in the nearby research facility, killing DuBois and Shapiro. Stratt tells Ryland that he must join the space mission, as there is no time to train another astronaut. In the present, Rocky and Ryland examine the sample from Adrian's atmosphere and discover it contains an Astrophage predator, which Ryland calls Taumoeba. Ryland seeks to breed a version of the Taumoeba that will survive on Venus and its equivalent near Erid, a planet he calls Threeworld. He presumes that the Taumoeba could eat the Astrophage and limit the dimming of the sun and the equivalent star in Erid's galaxy. The lights go out and Ryland realizes the Hail Mary's generators have failed. Ryland and Rocky discover that Taumoeba have infiltrated the fuel tanks and they are consuming the Astrophage. They return to the Blip-A to get more fuel. In a flashback, Stratt tells Ryland he must join the mission and she will drug him and force him if she has to.

In the present, Ryland remembers this and realizes he is not the hero he thought he was. He also realizes that his supply of food is very limited, since the Hail Mary was not intended to return to Earth. He successfully breeds Taumoeba that can survive on Venus and Threeworld. Ryland gives Rocky Taumoeba to take back to Erid and the two separate. In a flashback, Ryland is in a jail cell in Baikonur and he is visited by Stratt, who tells him that she is forcing him to take part in the mission because it is the only way to save the world.

In the present, Ryland realizes that some Taumoeba have escaped the tanks they were being kept in. He thinks the same must have happened on the Blip-A. If Rocky does not realize this, the Taumoeba will eat all of the Astrophage fuel. Ryland chooses to return to the Blip-A and save Rocky, even though this means he will not have enough food to get back to Earth. He rescues Rocky and the two take the Hail Mary to Erid. Ryland sends one of the beetles back to Earth, containing the Taumoeba that can survive on Venus.

In the final chapter, Ryland is living on Erid in a dome constructed for him by Eridian scientists, where they have replicated the Earth's atmosphere. Rocky tells Ryland that the sun has returned to its former brightness — he saved Earth. He asks Ryland if he plans to return home and Ryland says he is not sure. Ryland teaches a science class to Eridian children.