Brilliant but eccentric scientist Seth Brundle meets science journalist Veronica "Ronnie" Quaife at a meet-the-press event held by Bartok Science Industries, the company funding his work. He takes her back to the laboratory of his warehouse home and asks her to exclusively document his invention: two "telepods" that can teleport objects between them. While they can transport inanimate objects perfectly, they mutilate live tissue, as demonstrated when the pods turn a baboon inside out.
Seth and Ronnie continue experimenting with the device, developing a relationship in the process. Using two steaks, one a control and one teleported, Seth discovers that the machine is creating a synthetic version of biological material rather than the object itself. He reprograms the system to understand the makeup of living tissue and successfully teleports a second baboon. Ronnie departs before they can celebrate, and Seth worries that she is rekindling her relationship with her editor, Stathis Borans. She actually left to confront Stathis about a veiled threat, spurred by his jealousy of Seth, to publish the telepod story without her consent. While drunk, Seth teleports himself alone, unaware that a housefly had entered the transmitter pod with him. He emerges from the receiving pod, seemingly normal.
After Seth and Ronnie reconcile, Seth exhibits sugar cravings and increased strength, agility, stamina, and sexual potency, which he believes resulted from the teleportation "purifying" his body. Ronnie becomes increasingly concerned about Seth's deteriorating sanity, as well as sores on his face and strange, bristly hairs growing from a wound on his back. When she expresses her worries, Seth becomes aggressive, insisting that the process is beneficial. He tries to force Ronnie to undergo teleportation, but she refuses.
Seth goes to a bar and partakes in an arm-wrestling match, leaving his opponent with a compound fracture. He brings a woman back to the warehouse, where they have sex. Seth tries to coerce her into teleporting. However, Ronnie intervenes, and Seth throws her out. When his fingernails begin falling off, he realizes that something is indeed wrong. He re-runs the teleportation sequence and discovers that the computer, confused by the presence of two separate life forms in the sending pod, fused him with the fly at the molecular-genetic level.
Seth continues to deteriorate, losing body parts along with his human appearance. After several weeks, he reconnects with Ronnie and reveals he is becoming a hybrid of human and insect, which he has nicknamed "Brundlefly". He has also begun vomiting digestive enzymes onto his food, is able to cling to walls and ceilings, and is losing his human reason and compassion.
Seth installs a fusion program into the telepod computer, planning to dilute the fly genes in his body with human DNA. Ronnie discovers she is pregnant with Seth's baby and has a nightmare of giving birth to a giant maggot. She demands that Stathis persuade a doctor to perform an abortion in the middle of the night, but Seth abducts her before the procedure. He begs her to carry the child to term, since it may be the last remnant of his humanity. Stathis breaks into Seth's lab with a shotgun, but Seth disables him using his corrosive vomit to destroy Stathis' hand and foot, stopping just short of vomiting acid onto his face when Ronnie screams at him to stop.
Seth reveals to Ronnie he will use the telepods to fuse the two of them, along with the unborn child, into a single entity to become "the ultimate family". During a struggle, she tears off his jaw, which triggers his transformation into a monstrous, insectoid-human creature.
Seth traps Ronnie in the first telepod, puts himself in the other, and begins the countdown. Stathis recovers his shotgun and severs the cables connecting Ronnie's telepod to the computer. Seth breaks halfway out of his own pod, but the fusion process activates, gruesomely amalgamating him with a chunk of the telepod. Seth crawls to Ronnie and places the shotgun barrel to his head, silently begging her to put him out of his misery. She then tearfully fires, killing him, and falls to her knees in despair.
