Seth Brundle, a brilliant but eccentric scientist, meets Ronnie Quaife, a science journalist, at a press event. He takes her back to his warehouse home and laboratory and shows her his invention: a set of "telepods" that allows instantaneous teleportation between pods. Seth convinces Ronnie to keep the invention secret in exchange for exclusive rights to the story, and she documents his work. Although the telepods can transport inanimate objects, they mutilate live tissue, which is demonstrated when a baboon is turned inside-out during an experiment.
Seth and Ronnie begin a relationship. Their first sexual encounter inspires Seth to reprogram the telepod to understand the makeup of living tissue, and he 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; in reality, Ronnie has left to confront Stathis about a veiled threat, spurred by his jealousy of Seth, to publish the telepod story without her consent. Seth teleports himself alone, unaware that a housefly has slipped inside the transmitter pod with him. He emerges from the receiving pod seemingly normal.
Seth and Ronnie reconcile. Seth exhibits increased strength, stamina, and sexual potency, which he believes is a result of the teleportation "purifying" his body. He has sugar cravings and Ronnie is concerned about Seth's deteriorating sanity and also the strange, bristly hairs growing from a wound on his back. Seth becomes arrogant and violent, insisting that the teleportation process is beneficial, and tries to force Ronnie to undergo teleportation. When she refuses, he abandons her, goes to a bar and partakes in an arm-wrestling match, where he leaves his opponent with a compound fracture. He meets a woman named Tawny and brings her back to his warehouse. They have intercourse, and Seth tries to coerce her into teleporting. Ronnie rescues her from teleportation. Seth throws Ronnie out, but when his fingernails begin falling off, he realizes something went wrong during his teleportation. He checks his computer's records and discovers that the telepod computer, confused by the presence of two lifeforms in the sending pod, fused him with the fly at the molecular-genetic level.
Seth continues to deteriorate, losing body parts and becoming less human in appearance. After several weeks of being too scared to contact Ronnie, he reconnects with her and says he is becoming a hybrid of human and insect. He has nicknamed this "Brundlefly". He has also begun vomiting digestive enzymes onto his food to dissolve it and has gained the ability to cling to walls and ceilings. He realizes he is losing his human reason and compassion, driven by primitive impulses he cannot control.
Seth installs a fusion program into the telepod computer, planning to dilute the fly genes in his body with human DNA. Ronnie learns that she is pregnant by Seth and has a nightmare of giving birth to a giant maggot. She has Stathis persuade a doctor to perform an abortion in the middle of the night. Having overheard their conversation, Seth abducts Ronnie before the abortion can take place and 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 disfigures him with his corrosive vomit.
Seth reveals his desperate plan to Ronnie: he will use the telepods to fuse himself and her, together with their unborn child, into one entity. As Seth drags her into one of the telepods, she accidentally rips off his jaw, triggering his final transformation into an insectoid-human creature, which bursts from Seth's decayed human skin. It traps Ronnie inside the first telepod and enters the other. The wounded Stathis uses his shotgun to sever the cables connecting Ronnie's telepod to the computer, allowing Ronnie to escape. Breaking out of its own pod just as the fusion process is activated, the creature is gruesomely fused with the metal door and cabling of telepod 2. As the deformed creature crawls out of the receiving pod, it silently begs Ronnie to end its suffering, and she tearfully shoots it.
