Following the events of the Battle of Installation 05 and John-117's escape onto the Forerunner dreadnought, The crew of the dreadnought attempt to kill the Master Chief while John attempts to assassinate the Prophet of Truth. He is unable to kill Truth, and the crew believes John is killed. Thinking the threat is gone, the dreadnought approaches Earth, and John escapes the ship, performing an orbital drop onto Earth's surface.
Uprising primarily focuses on the efforts of John-117 to kill the Prophet of Truth aboard the Forerunner Dreadnought.
Uprising takes place primarily on the Anodyne Spirit as the Prophet of Truth heads towards Earth and the Portal at Voi.