The game is set during the Raccoon City outbreak, which forms the backdrop for the events of Resident Evil 2 and Resident Evil 3: Nemesis. File #2 runs parallel to those stories but focuses on different characters — a group of average citizens trying to escape the doomed city.

Each scenario shows a new area or event during the fall of Raccoon City, deepening the lore and giving players a ground-level view of the chaos through the eyes of untrained survivors.