The story of the game takes place in space. After the crew of the USG Ishimura was killed by a horde of vicious zombies after the ship's distress signal was ignored, the remaining survivors decided to stay in space and wait for help. As they waited, they began to receive mysterious signals from an unknown source.

After investigating the signals, they discovered that the source was actually the planet Earth. The crew sent a message to the Earth, and a few brave people answered. They decided to send a rescue crew to the Earth, and they also sent a message to the USG Ishimura, informing them of their discovery.

The USG Ishimura is the most advanced ship in the entire universe, and the most powerful ship ever built. It has a powerful arsenal of weapons and defenses. It can withstand a great deal of damage, and it can easily be destroyed by a single hit.