AMY takes place in December 2034 in the small town of Silver City (Midwest, USA) after a comet strikes, wreaking havoc on humanity and unleashing a deadly virus that has infected almost everyone. Players take on the role of Lana, who regains consciousness in the midst of all the mayhem. The world she once identified with seems to have been torn to Hell, and most of the people she knew have now become part of a wild horde. Lana feels the virus beginning to infect her and knows she must run as far as possible to escape the nightmare. The presence of the titular Amy, a seemingly defenseless eight-year-old autistic girl who has curious powers, forces her to make choices that will affect both their lives. Together, they must fight or run from the infected humans, demons and the military, in the hope of not only saving each other, but also the future of humanity.

The cooperative gameplay featured in AMY is a deep and unique system that requires players to strategize in order to protect Amy and keep both characters alive . Unlike other games with a secondary character, Amy is neither a super warrior, nor a docile character that follows along. Players must use Amy's size and special abilities to their advantage by keeping her close in order to ward off the virus, and having her complete tasks that Lana can't. For both to survive, Lana must stop at nothing to keep Amy safe.

In addition to the unique co-op gameplay, AMY features original stealth-action elements and an emphasis fierce melee combat. Because Lana and Amy are often weaker than their enemies, players must choose to fight, or escape by running, pushing enemies away or hiding until the creatures depart. Adding yet another twist to the gameplay, players must balance Lana's level of infection in order to navigate monster-ridden areas. When Lana allows herself to succumb to the virus by separating herself from Amy, she is no longer attacked by the bloodthirsty creatures. But if she's exposed too long without protection, she will not make it through alive.