Two years have passed since the final battle with Sephiroth. Though Midgar, city of mako, city of prosperity, has been reduced to ruins, its people slowly but steadily walk the road to reconstruction. However, a mysterious illness called Geostigma torments them. With no cure in sight, it brings death to the afflicted, one after another, robbing the people of their fledgling hope.

U.S. federal agent Leon S. Kennedy sneaks into the "East Slavic Republic" to verify rumors that Bio-Organic Weapons (BOWs) are being used in the country's civil war, which the U.S. and Russia are making preparations to jointly intervene in. Right after his infiltration, the U.S. government orders him to leave immediately. Determined to uncover the truth, Leon ignores the order and enters the battlefield to end the chain of tragedies caused by the BOWs.