Seth Brundle, a brilliant but eccentric scientist, meets Veronica “Ronnie” Quaife, a science journalist, at a press event held by Bartok Science Industries. He takes her back to his warehouse home and laboratory and shows her his invention: a set of “Telepods” which allow instantaneous teleportation from one pod to another. Seth convinces Ronnie to keep the invention secret in exchange for exclusive rights to the story, and she begins to document his work. Although the Telepods can transport inanimate objects, they are unsuccessful with living flesh, as is demonstrated when a baboon is turned inside-out during an experiment.

Seth and Ronnie begin a romantic relationship. Their first sexual encounter inspires Seth to reprogram the Telepod computer to cope with organic matter, 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 and former lover, Stathis Borans; in reality, Ronnie has left to confront Stathis about a veiled threat, spurred by romantic jealousy, to publish the Telepod story without her consent. Drunk and jealous, Seth rashly decides to teleport 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, and Seth soon begins to exhibit increased strength, stamina, and sexual potency, which he believes is a result of the teleportation “purifying” his body. Ronnie, however, is more concerned about Seth’s growing mania, sugar cravings and the strange, bristly hairs growing from a wound on his back. Seth quickly becomes arrogant and violent, insisting that the teleportation process is like a beneficial drug, 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 at the bar and brings her back to his warehouse for sex. However, Ronnie arrives in time to prevent Seth from forcibly teleporting her. Refusing to listen to Ronnie’s concerns about his health, Seth throws her out, but when his fingernails begin falling off, he realizes something went horribly wrong during his teleportation. He checks his computer’s records and discovers that the computer, confused by the presence of two life-forms in the sending pod, fused him with the fly at the molecular-genetic level.

Over the next few weeks, Seth continues to deteriorate, losing body parts and becoming less human in appearance. He reconnects with Ronnie and theorizes that he is becoming a hybrid of human and insect, which the doomed Seth dubs “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. Seth realizes he is losing his human reason and compassion, and is slowly becoming driven by primitive impulses that he cannot control. Unable to cope with the situation, Ronnie turns to Stathis Borans for support.

Seth installs a fusion program into the Telepod computer, and plans to dilute the fly genes in his body by adding more human DNA. Ronnie learns that she is pregnant by Seth, and has a nightmare of giving birth to a giant maggot. Ronnie visits Seth, but finds herself unable to tell him about the pregnancy. However, Seth overhears Ronnie convincing Stathis to persuade a doctor to perform an immediate abortion. He abducts Ronnie from a clinic 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 dissolves Stathis’ hand and foot with his corrosive vomit.

Seth then reveals his desperate plan to Ronnie: he will use the Telepods to fuse himself, Ronnie, and their unborn child into one entity, so they can be “the ultimate family”. As Seth drags her into Telepod 1, Ronnie accidentally rips off his jaw, triggering his transformation into the final “Brundlefly” creature, which bursts out from Seth’s decayed human skin. Brundlefly traps Ronnie inside Telepod 1 and enters Telepod 2. The wounded Stathis uses his shotgun to sever the cables connecting Telepod 1 to the computer, allowing Ronnie to escape unharmed. Breaking out of its own pod just as the fusion process is activated, Brundlefly is gruesomely fused with a chunk of Telepod 2 itself. As the mortally-wounded Brundlefly/Telepod-fusion creature crawls out of the receiving pod, it silently begs Ronnie to end its suffering with Stathis’ shotgun. Ronnie hesitates for a moment, then blasts Brundlefly’s head off before falling to her knees in tearful anguish.