The film interweaves the mansion incident from the first game with the city outbreak from Resident Evil 2, so both happen on the same night. Claire's warnings about Umbrella turn out to be right. The company's experiments, carried out on the town and linked to the orphanage where the Redfields grew up, released the infection. Chris's affection for William Birkin makes the reveal of Umbrella's crimes a personal betrayal as well.
Inside the S.T.A.R.S. team, Wesker's hidden loyalties show that the rot has spread to the institutions meant to protect the town. In the end the corporation treats the whole city as disposable. The survivors, the reunited siblings, Jill and Leon, have to escape Raccoon City before it is wiped out, and the final escape is by train.
Read in hindsight, the orphanage details, the infected neighbor's diary-like scrawl and Chris's defense of Birkin all point to the same point: the horror was engineered, not natural. The ending sets up a larger conspiracy for a sequel that was later cancelled.