The film is set during fictitious space shuttle mission STS-157. Dr. Ryan Stone (Sandra Bullock) is a medical engineer aboard the Explorer for her first space shuttle mission. Her companion is veteran astronaut Matt Kowalski (George Clooney), commanding his final expedition. During a spacewalk to service the Hubble Space Telescope, Mission Control in Houston warns the team about a Russian missile strike on a defunct satellite, which has caused a chain reaction forming a cloud of debris in space. Mission Control orders that the mission be aborted and the shuttle begin re-entry immediately. Communication with Mission Control is lost shortly after.

High-speed debris from the Russian satellite strikes the Explorer and Hubble, and detaches Stone from the shuttle, leaving her tumbling through space. Kowalski, using a Manned Maneuvering Unit, soon recovers Stone and they make their way back to the Space Shuttle. They discover that it has suffered catastrophic damage and the crew is dead. They use the thruster pack to make their way to the International Space Station (ISS), which is in orbit only about 1,450 km (900 mi) away. Kowalski estimates they have 90 minutes before the debris field completes an orbit and threatens them again.