From the afterlife, Mary Shelley explains that she has a story she wanted to tell after Frankenstein but could not due to her death. To tell it, she possesses Ida, Jessie Buckley, a woman living in 1936 Chicago, who in her trance proceeds to discuss the criminal activities of crime boss Lupino. Lupino's henchmen Clyde and James discreetly kill her afterward.
Elsewhere in Chicago, Frankenstein's monster, AKA "Frank" Christian Bale arrives at the house of scientist Dr. Cornelia Euphronius, Annette Bening. Having read about Euphronius' work on reanimation, he enlists her to create a companion for him after a century of loneliness. Euphronius and Frank choose Ida's corpse and successfully revive her, but she loses her memory in the process. Frank takes advantage of this and states that she is his Bride and lost her memory in an accident, which she accepts.
Frank and the Bride go to the cinema to see a movie featuring Frank's favorite actor Ronnie Reed, Jake Gyllenhaal, and then go dancing at a club. As they leave, two men harass the Bride and Frank retaliates by killing them. He tells the Bride to leave him, but she decides to live life as a runaway with him. They stow away in a train to New York City, killing a security officer who finds them as the train passes through Indiana. Meanwhile, Detective Jake Wiles, Peter Sarsgaard, and his assistant Myrna Malloy, Penélope Cruz, investigate the murders and eventually follow them to New York.
Frank and the Bride cause chaos in a screening of Revolt of the Zombies and then seek refuge from the police and an angry mob at a high-class party. Frank runs into Ronnie Reed and expresses his adoration, but is dismissed. Detective Wiles and the police arrive at the party, but fall back when the Bride briefly holds Reed at gunpoint. Wiles recognizes her real identity as Ida. The Bride and Frank kill a police officer, hot-wire a car, and manage to escape the city.
The Bride and Frank's crime spree becomes well-publicized and Lupino recognizes her in a newspaper. He executes James for failing to silence her and dispatches Clyde to kill her again. Meanwhile, Malloy makes a connection between reports of murders/sightings of the pair in cities where Reed's films were set. This prompts Malloy and Wiles to travel to Niagara Falls where they find the couple just as Frank asks the Bride to marry him. Wiles confronts the Bride and informs her of her true identity as Ida. She injures him in response. As Frank and the Bride flee, Frank admits that he was deceptive toward her in the beginning and conveys that he actually did not know who she was before she died, and she forgives him.
Wiles explains to Malloy that he and Ida were planning to take down Lupino and expresses guilt that his inaction led to her death. He decides to retire and promotes Malloy as his replacement. Malloy tracks Frank and the Bride to a drive-in theater in Illinois. At the same time, Clyde arrives and fatally shoots Frank in the head. The Bride escapes with Frank's body and returns to Euphronius' laboratory, unaware that Malloy is following her. Euphronius declares that she is incapable of reviving Frank. Clyde breaks into the laboratory and fatally shoots the Bride before leaving. The police arrive before Malloy orders them to search for Clyde, leaving Euphronius with the Bride and Frank's corpses. Seemingly possessed by Shelley's spirit, Euphronius decides to revive the couple. Outside, the police arrest Clyde for killing the Bride and Frank. Malloy sees bright lights shine from the laboratory. Inside, the revived corpses hold hands.
During the credits, Lupino is apprehended by Wiles and the female rioters who were inspired by the Bride's rants.
