Delirium is set in Portland, Maine, 64 years after love (amor deliria nervosa or delirium) has been declared a disease by the U.S. government. Seventeen-year-old Lena Holoway is looking forward to her 18th birthday, when she can have the mandatory medical procedure that renders patients incapable of love. Lena believes the procedure, or cure, will allow her to lead a safe and conventional life.
A few months prior to having the procedure done, Lena undergoes an interview evaluation that the government will use to match her with a spouse. During her evaluation (which goes poorly), the building is overrun by a stampede of cows that have been unleashed on the facility by invalids, uncured and unregulated rebels living on the outside the city’s fences. While the cows overrun her evaluation room, Lena sees a boy laughing in the observation deck, and she believes that he is responsible for the situation. Lena is relieved that her evaluation is nullified and rescheduled so she can have a second chance at a better score. A higher score leads to a better match and better jobs.
While jogging, Lena and her friend Hana meet a guard, Alex, the same boy Lena saw in the observation deck, patrolling the city’s fence. Lena is surprised that Alex is cured and not an invalid. Lena does not see Alex again for several weeks, until she reluctantly goes to an illegal party in the outskirts of the city to find Hana. Lena and Alex talk and dance, and he asks her to meet him at the beach by the city the following day. Lena is not afraid of spending time with Alex because he is cured, and she can’t catch deliria from him.
While at the beach, Lena confides in Alex and tells him that the government attempted to cure her mother several times but the procedure did not work, and she eventually committed suicide. Alex confesses to Lena that he was born in the Wilds, the unregulated areas outside of the city, and he has never had the procedure. He tells her that he really likes her, and he does not want to lie to her anymore. Furious and afraid, Lena runs from Alex, and for days afterward, she checks herself for symptoms of the disease. She tries to go about her days as normal as possible, successfully retaking her evaluation and receiving the list of boys that the government has approved for her to be matched with.
One night, regulators go from house to house checking for illegal activity. While the regulators bypass Lena’s house, she is concerned that Hana is at an illegal party. Lena sneaks out to find and warn her. At the party, Lena does not find Hana, but the regulators come and attack the teens at the party. A regulator’s dog mauls Lena’s leg, but Alex, who is at the party, saves her life.
After the raid, Alex and Lena secretly spend time together, meeting at an abandoned house. She realizes that she has caught deliria, but she no longer cares. Through careful planning and with the help of other sympathizers, Lena crosses over into the Wilds to the place where Alex lives. After they come back, Lena feels changed, but the time before her cure is running short.
Alex tries to convince Lena to escape to the Wilds permanently with him, but she is afraid to leave her family. As she is talking to him about her mother, Alex realizes Lena’s mother may not be dead; she may be locked in the Crypts, a prison where the government keeps the insane, criminals and dissenters. Alex regularly goes to the prison because his father is buried in the Crypt’s small graveyard. While visiting, he may have seen Lena’s mother. Using his fake identification as a guard, he takes Lena there under the pretense that she needs to be shown the consequences of deliria. At the prison, they find out that Lena’s mother never committed suicide but was locked up in the Crypts for years before she escaped into the Wilds.
Realizing that everyone in her family has lied to her, Lena is angry. She agrees to leave Portland with Alex. The night they are to escape, regulators show up at their meeting place and chase them. Alex escapes, but Lena is caught and taken home where she is sedated and restrained. Her procedure is rescheduled to take place in two days.
With Hana’s help, Lena gets a message to Alex. The night before the cure, Lena works on her restraints, and just before dawn, she gets free. Lena realizes there is no way to find Alex in the city and no way to escape to the Wilds on her own. She contemplates going to the ocean to commit suicide, deciding that she would rather die her way than live theirs. As she is escaping through the window, Alex shows up on a motorcycle.
Lena and Alex lead the regulators and police on a high-speed chase through the city, where they are shot at. Realizing that they both won’t be able to escape over the fence, Alex gives himself up so Lena can escape into the Wilds. The last time Lena sees Alex, he has been shot as an army of men descend on him. She escapes to the Wilds alone.