Seth Brundle (Jeff Goldblum), a brilliant but eccentric scientist, meets Veronica Quaife (Geena Davis), a journalist for Particle magazine, at a meet-the-press event held by Bartok Science Industries, the company that provides funding for Brundle's work. Seth shows Veronica a project that will change the world: a set of "Telepods" that allows instantaneous teleportation of an object from one pod to another. Veronica eventually agrees to document Seth's work. Although the telepods can transport inanimate objects perfectly, they do not work correctly on living things, as is horrifically demonstrated when a live baboon is turned inside-out during an experiment. Seth and Veronica begin a romantic relationship, and their first sexual encounter provides inspiration for Seth, who sets about successfully reprogramming the telepod computer to cope with living flesh.
Seth then succeeds in teleporting a second baboon with no apparent harm. Flushed with this success, Brundle wants to spend a romantic evening with Veronica, but she suddenly departs before they can celebrate. Brundle's judgment soon becomes impaired by alcohol and his paranoid fear that Veronica is secretly rekindling her relationship with her editor and former lover, Stathis Borans (John Getz). In reality, Veronica has left to confront Borans about a veiled threat of his (spurred by his romantic jealousy of Brundle) to publish the Telepod story without her consent. A drunk and jealous Brundle decides to teleport himself as revenge for Veronica's seeming infidelity, but a common housefly slips into the pod, unseen. The teleportation successful, Brundle emerges from the receiving pod, seemingly normal. Shortly after his teleportation, Seth begins to exhibit what at first appear to be beneficial effects of the process—such as increased strength, stamina and sexual potency. However, he soon becomes arrogant and violent, and eventually realizes that something went horribly wrong when his fingernails begin falling off. Brundle checks his computer's records, and discovers that the telepod computer, confused by the presence of two separate life-forms in the sending pod, merged him with the fly at the molecular-genetic level.
Over the next few weeks, Brundle continues to deteriorate, becoming progressively less human in appearance. He theorizes, that he is slowly becoming a hybrid creature that is neither human nor insect (which the doomed Seth begins referring to as "Brundlefly"). He has started to exhibit fly-like characteristics, such as vomiting digestive enzymes onto his food in order to dissolve it, and the ability to cling to walls and ceilings. Brundle comes to realize that he is losing his human reason and compassion, and that he is now being driven by primitive impulses he cannot control. Attempting to find a cure for his condition, Brundle installs a fusion program into the telepod computer in order to possibly dilute the fly genes in his body with more pure human DNA. To her horror, Veronica learns, that she is pregnant by Seth and she cannot be sure if the child was conceived before or after his fateful teleportation. The rapidly-deteriorating Brundle abducts Veronica from a clinic before she can get an abortion, and begs her to carry the child to term, since it could potentially be the last remnant of his untainted humanity. Veronica sadly refuses, afraid that the child will be a hideous mutant. Meanwhile, Stathis Borans breaks into Brundle's lab with a shotgun and comes to Veronica's rescue, but is seriously injured and nearly killed by the almost fully-transformed Brundle, who dissolves Borans' left hand and right foot with his corrosive vomit-drop enzyme.Brundle then reveals his desperate, last-ditch plan to Veronica—he will use the three telepods (the third pod being the original prototype) to fuse himself, Veronica, and their unborn child together into one entity, so they can be the "ultimate family". Veronica frantically resists Brundle's efforts to drag her into Telepod 1 and then accidentally tears off his jaw, triggering his final transformation into a monstrous combination of man and insect. The "Brundlefly" creature traps Veronica inside Telepod 1, then steps into Telepod 2. However, the wounded Stathis manages to sever the power cables connected to Veronica's telepod with his shotgun, allowing Veronica to escape unharmed. Breaking out of its own pod as the fusion process is activated, Brundlefly is gruesomely fused with chunks of metal and other components from Telepod 2. As the mortally-wounded Brundlefly-telepod fusion creature crawls out of the receiving pod, it silently begs Veronica to end its suffering with Borans' shotgun. A devastated Veronica hesitates for a moment, and then pulls the trigger, ending the life of her hideously-transformed lover before falling to her knees in anguish.
- Jeff Goldblum as Seth Brundle
- Geena Davis as Veronica Quaife
- John Getz as Stathis Borans
- Joy Boushel as Tawny
- Leslie Carlson as Dr. Brent Cheevers
- George Chuvalo as Marko
- David Cronenberg as Gynecologist
The movie was a commercial success and was also one of the most successful ones of David Cronenberg.