Game Over starts with a serial killer (whose face is not revealed) stalking a girl with cancer from outside her house and later at midnight killing her by wrapping her head in plastic and tying her hands behind her. After that he takes her to an abandoned field where he beheads her and sets her body on fire.
Later, the film focuses on Swapna (Taapsee Pannu) who is a single young woman and also a talented game designer. She has a fear of the darkness, and also suffers from post-traumatic stress more so known as 'anniversary reaction', a condition, which triggers unsettling feelings around the anniversary of a traumatic event. For Swapna, it is the horrific memory of her rape that took place on last New Year's Eve.
It's her second time that she suffers from the uncontrollable feeling whenever she enters darkness; the first time was one year ago, the following days after she was raped. Her symptom starts when she feels pain at her wrist, where there is a tattoo she got one year ago. As she got the tattoo too long ago, it was explained technically impossible by a doctor that the pain was caused by it, but only she knows there's connection between the tattoo and her miserable memory. Her family have a traditional mind that think decent girls shouldn't have tattoo or go out in the night; she didn't listen, and was later raped. Instead of encouraging her afterward, her parents kept blaming the tragedy on her, for having a tattoo and going out in the night.
Because of this, she leaves her parents, never contacted them since, and leads a secluded life with Kalamma (Vinodhini Vaidyanathan), a housemaid who stays with her. Her only solace is her love for gaming. Swapna later learns that her tattoo ink was mixed with a stranger's ash, because of a mistake by the tattoo artist. She begins to have some bizarre dreams and finds that the girl Amutha (Sanchana Natarajan), a cancer survivor, was an unfortunate victim of a serial killer. Amutha's mother tells Swapna that her daughter will always be with her and want her to fight.
The same serial killer that killed many young women in the city, including Amutha, finally targets Swapna, who is now temporarily a wheelchair user due to an attempted suicide. The killer kills Mr Anwar, the security of her house, and Kalamma, and finally Swapna. But before Swapna is killed, she is surprised to find that she has three the same tattoo pattern on her wrist, which she had only one.
Swapna wakes up from the "nightmare", but finds now only two tattoo patterns are left on her wrist. She now realizes that she was not killed in a dream, but it's Amutha's spirit, who wants Swapna to fight, that gave her three lives, just like video games she's often playing. And now Swapna has lost one life, with two remaining.
To avoid the same mistake that got them all killed in her first life, Swapna, who is now using her second life, call the police and stay in the house with Kalamma to wait for the police. Police arrive in time and shoots the killer before the latter kills Swapna and after, however, kills Kalamma. She seems to be saved and is taken by the police to the station. But on their way, their vehicle is exploded by a bomb set by the killers. It is now revealed that there was not only one killer that was trying to kill her, but three.
Swapna now is using her third, also the last life to fight against the killers. Encouraged by Amutha's spirit, Swapna conquers her fear for darkness. She does not turn on the light to draw the killers' attention. Swapna and Kalamma manages to kill the first killer by setting fire on him. The second killer almost kills the both but is also taken down by them. The third killer beats Kalamma to unconsciousness and confronts Swapna, who manages to stab him to death with a piece of broken mirror.
