A year after a supermoon’s light activated a dormant gene, transforming humans into bloodthirsty werewolves and causing nearly a billion deaths, the nightmare resurfaces as the supermoon rises again. Two scientists attempt to stop the mutation but fail and must now struggle to reach one of their family homes.

Steve McGarrett returns home to Oahu, in order to find his father's killer. The governor offers him the chance to run his own task force (Five-0). Steve's team is joined by Chin Ho Kelly, Danny "Danno" Williams, and Kono Kalakaua.