NOTE: This spoiler was submitted by Jeremy.
Jerry Hickfang (Ryan Reynolds) works at a factory that manufactures and distributes toilets. His boss calls him over and asks him to help plan the upcoming company picnic. Jerry happily agrees. After work, he goes to his home above a bowling alley where he lives with his dog and cat, Bosco and Mr. Whiskers (both voiced by Ryan Reynolds). He hears them talking to him as a result of his refusal to take prescribed medication. Mr. Whiskers speaks with a Scottish accent and frequently insults and belittles Jerry, while Bosco is supportive and cares for Jerry. Even with his pets, Jerry feels a lingering sense of loneliness.
Jerry frequently visits his psychotherapist Dr. Warren (Jacki Weaver). We learn that Jerry's mother also had a history of mental illness following her move from Berlin to America. She also heard voices, and Warren tries to avoid the same happening with Jerry.
At work, Jerry gathers with a committee to plan a party at the company. Jerry sees his crush, an English woman named Fiona (Gemma Arterton) planning with everyone else. She suggests they do a conga line in the hall. Jerry watches with astonishment as Fiona dances.
Jerry joins Fiona, along with two other co-workers, Lisa (Anna Kendrick) and Alison (Ella Smith), at a bar. Fiona comes off a bit snooty when talking about how she moved from England to America with a boyfriend, only to get dumped by him, and now she wants to leave America as soon as she can. Lisa shows interest in Jerry and implies that she needs a ride, but he wants to give Fiona a ride home instead. Jerry takes Fiona home and invites her to a Chinese food restaurant.
Fiona stands Jerry up at the restaurant and joins her co-workers for karaoke night at a bar, leaving Jerry alone (as in, the only customer in the entire restaurant). Afterward, Fiona's car is unable to start. Jerry comes around and finds her, and he gives her a ride. She apologizes for standing him up, saying she left him a message. To make it up, she suggests they go get burgers.
While driving, Jerry tries to flirt with Fiona, saying she came from Heaven. He gives her some trivia on the names of four angels. Because he's distracted, Jerry doesn't see a deer in the road and accidentally rams into it. The deer's head goes through the windshield, and Jerry hears the deer speak to him and beg him to put it out of its misery. Jerry slashes the deer's throat, to Fiona's horror. She runs from the car into the woods. Jerry chases after her with his knife, accidentally tripping and plunging the knife into her stomach. Fiona is choking on her blood while an apologetic Jerry stops her suffering by sticking the knife in her heart. He goes home and tells his pets what he did. Mr. Whiskers suggests that he wanted to kill Fiona, otherwise he wouldn't have taken the knife with him. The cat convinces Jerry to go back into the woods and gather her remains. Jerry does so and cuts Fiona to pieces, keeping her head in the fridge.
Jerry starts to hear Fiona's head speaking to him. She comes off awfully chipper despite being a severed head. Jerry then decides to heed Dr. Warren's advice and to keep taking the medication. However, it bothers him when he can't hear Bosco and Mr. Whiskers, and he opens the fridge to see Fiona's head, bleeding and decomposing. He dumps the medication down the sink. When the voices return, Mr. Whiskers goads Jerry into finding a new victim to kill since he believes it made Jerry feel good about himself, while Bosco disagrees and says the cat is sick and disturbed.
Jerry invites Lisa out for a drink later that night. They hit it off and she invites him back to her place. He instead drives to his childhood home. We see through flashbacks that Jerry's father was abusive and didn't want anything to do with him or his mother. Jerry's mother was also disturbed, and when she heard the sirens coming for her, she tried to cut her throat with a shard of glass. She begged Jerry to finish it for her, and he tearfully obliged. This resulted in him being institutionalized. Jerry cries as he remembers this. Lisa consoles him and they kiss. She spends the night with him.
Jerry and Lisa start to make out at work until Alison interrupts them. Jerry leaves, and Lisa asks Alison to find Jerry's address so she can bring him a surprise.
Lisa goes to Jerry's place that night while he's talking to his pets and Fiona's head. He panics and covers Fiona's head with his jacket. He answers the door and accidentally locks himself out. He goes to the roof to get in through the skylight, while Lisa picks the lock with a hairpin. She sees all of Fiona's stored remains and sees her hair sticking out from under Jerry's jacket, which Jerry sees from the skylight. He tries to assure her that nothing's wrong, but Lisa is very freaked out. She locks herself in Jerry's bathroom for a while until she relents and leaves. Jerry grabs her and throws her against the bedpost, breaking her neck. He then decapitates her and stores her head next to Fiona's.
Alison and two other co-workers worry as they can't reach Lisa or Jerry the next day at work. They look up an article online that mentions Jerry being institutionalized as a child. Alison later goes to Jerry's home that day. It then cuts to Jerry storing her head along with Fiona's and Lisa's. With all the collective voices driving him nuts, Jerry goes to Dr. Warren's office and confesses to the murders. She tries to contact help, but Jerry knows she is going to have him committed again. He puts tape on her mouth and ties her wrists and feet together before taking her to his place.
Meanwhile, the other two co-workers arrive at Jerry's place and find both Alison's and Lisa's cars. One of them opens the door, letting Bosco out. The man sees the grisly scene in the house and barfs before telling the other man to call the cops.
Jerry takes Warren to his home, where Mr. Whiskers says that Bosco got hit by a minivan (whether this is true or a joke isn't confirmed). The police arrive at Jerry's home, forcing him to escape. He goes down a chute and breaks a gas pipe as the cops throw tear gas canisters through the windows. They find Warren and wheel her out safely and also recover Mr. Whiskers. Jerry walks through the bowling alley as the cops find the broken pipe, causing an explosion. The bowling alley starts to fill with smoke, and Jerry collapses, breathing slowly before he presumably dies.
We see Bosco and Mr. Whiskers in a white area. Mr. Whiskers admits his respect and admiration for Bosco, which he reciprocates. They know it is time to part ways. Then we see Jerry dressed in a colorful outfit, accompanied by his parents, Fiona, Lisa, Alison, and even Jesus Christ. They all sing and dance happily, all of them at peace.