In the year 20XX, an outbreak of a robotic-virus known as the "Roboenza" runs rampant across the globe, infecting and disabling robots, hampering daily life for humans. Roll becomes infected with the virus, and the situation becomes worse as time passes and a cure is not found. One month after the outbreak, several infected robots become berserk and attempt to take over the world. One day, Dr. Wily appears in Dr. Light's lab with his capsule damaged and asks for help. Mega Man saves Wily from crashing and Wily says that Roboenza-infected robots attacked his spaceship and stole the parts to a medicine-making machine he had been working on to cure the virus. Mega Man agrees to retrieve the stolen parts from the eight Robot Masters. Before he begins, Proto Man arrives to help Mega Man, believing the job to be too big for just one of them and the two join forces to acquire the cure.

After taking down four Robot Masters, Dr. Wily presents what he claims is a prototype cure for Roll and asks if Mega Man is feeling Roboenza symptoms, to which Mega Man says he's feeling fine. After the last one is defeated, Mega Man comes down with Roboenza and is nearly incapacitated as Dr. Wily reveals that it was him behind the disease and that all robots who want the cure must serve under him. Roll gives her sample of the cure to Mega Man, who recovers and goes after Wily. During the fortress raid, Proto Man comes down with Roboenza as well, only to be saved by Mega Man who acquired an extra sample of the cure.