The titular main character, Omori, awakens in "White Space", a barren void he has lived in "for as long as [he] can remember". He enters a door to the vibrant world of "Headspace", where he meets his friends, Aubrey, Kel, Hero, Basil, and his older sister Mari. They peruse Basil's photo album, containing pictures of their shared memories, and decide to visit his house. Once they arrive, Kel and Aubrey scuffle, damaging the album. Upon seeing an unfamiliar photo fall from it, Basil panics and Omori is abruptly teleported back to White Space. He stabs himself with his knife, revealing the previous events to be the dreams of a teenage boy, Sunny, as he wakes up in the middle of the night.
The player discovers that Sunny and his mother are moving. He goes downstairs for a midnight snack but is confronted by a nightmarish hallucination. He dispels the illusion by taking deep breaths and returns to bed. Awakening once again in White Space, Omori reunites with Aubrey, Kel, and Hero. They discover that Basil has gone missing and set out to rescue him. The four explore the various regions of Headspace in search of Basil, with Mari assisting along the way. The group is continuously diverted from their search by various situations, leading their memory of Basil to gradually fade away.
Later, in the real world, it is revealed that Mari supposedly committed suicide four years ago, leading to the friend group diverging. Although Kel and Hero managed to recover to varying degrees, Sunny became an estranged shut-in, Aubrey a delinquent, and Basil an anxious recluse. Kel knocks on Sunny's door in an attempt to reconnect one last time. The player can either ignore Kel or answer the door: if they choose the former, Sunny stays inside for the remaining three days, immersing himself in housework and his dreams.
If the latter option is chosen, Sunny and Kel venture outside to find Aubrey and her new friends bullying Basil. The two discover that she has stolen Basil's real-life photo album, ostensibly to stop him from vandalizing it. After confronting Aubrey, they return the album to Basil, though some photos are missing. As he believes Sunny needs it more, Basil lends the album to him. While eating dinner together, Basil becomes mortified as he learns of Sunny's impending departure and runs to the bathroom. Sunny finds him in a hallucinatory panic attack, but leaves him alone out of fear. The next day, Kel and Sunny encounter Aubrey and her gang surrounding Basil at their old hangout spot. After they confront her, Aubrey angrily pushes Basil into a lake. Sunny dives in to rescue him, but both boys are saved from drowning by the arrival of Hero, and they carry him back to Basil's guardian, Polly.
Kel and Hero offer to have a sleepover in Sunny's house. While in his sleep, they return to Basil's now-dilapidated house, where Omori is transported to the more disturbing "Black Space". Basil appears in different areas, repeatedly attempting to talk to him about something before dying gruesomely each time. In the final room, Omori kills Basil and places himself atop a throne of massive, red hands. On the last day before Sunny's departure, the others reconcile with Aubrey, discovering she had kept the photos containing Mari from the album. Coming to terms with Mari's death, Sunny's friends decide to spend their final night together at Basil's house, despite him refusing to leave his room.
Eventually, in his dreams, Sunny finally confronts the truth about Mari's death: in an argument before their recital, he accidentally pushed Mari down their staircase, causing her demise. In denial that Sunny did it, Basil helped frame her death as suicide by hanging her corpse. As they finished, they glanced at Mari's body and saw an open eye staring back at them, shaping their subsequent hallucinations. While Basil was consumed by guilt and self-loathing, Sunny's suicidal depression led him to create Headspace and his alter ego Omori to repress his trauma. To prevent the truth being rediscovered, Omori resets Headspace every time memories of the incident resurfaced; Sunny then wakes up in the middle of the night, leaving the player with the choice of either confronting Basil or falling back asleep.
