Seymour Krelboyne (Jonathan Haze) is a clumsy assistant at an unassuming flower shop on the dreary Skid Row in Los Angeles. His boss, Gravis Mushnick (Mel Welles) is constantly frustrated with him, and is on the verge of firing him. Seymour's co-worker, the beautiful and sweet Audrey Fulquard (Jackie Joseph) begs Mushnick to give Seymour another chance. A customer, Burson Fouch (Dick Miller), who has visited countless florist shops to indulge his flower-eating habit, advises them to feature more strange and unusual plants to attract more business. Mushnick is desperate for more customers, since their only steady client is the elderly Mrs. Shiva (Leola Wendroff), who buys flowers for the funerals of her constantly-dying relatives. Seymour mentions that he had been developing an odd new plant, a cross between a venus flytrap and a butterwort. Mushnick makes him a deal: if the new plant brings in more business, Seymour may keep his job. A hopeful Seymour rushes home to get the plant.
Seymour lives in an apartment with his hypochondriac mother, Winifred (Myrtle Vail). The plant, potted in a coffee can, is a strange vertical pod surrounded by leaves. After bringing it back to the shop, Mushnick agrees it is interesting, but notices it looks sickly. Seymour promises to nurse it back to health, although he is unsure of how to feed it since water, sunlight, and high-quality plant food have seemed to do no good. Seymour shyly admits that he named the plant "Audrey Junior" after his crush. The original Audrey is delighted.
Alone in the shop that night, Seymour continues to study the plant. Every night at sunset, its pod opens like a mouth. Seymour accidentally pricks his finger on another thorny plant and Audrey Jr's pod opens wider. Seymour now understands that the plant feeds on human blood. Desperate to save it, Seymour gives it a few drops from his finger and leaves for the night. The next morning, Audrey Jr has grown dramatically, and customers begin flocking in to see the strange new attraction. Though he is becoming increasingly weak, Seymour feeds the plant blood from his own fingers every night. He refraines from telling anyone the secret behind Audrey Jr's health.
A dizzy and anemic Seymour can no longer provide his own blood for the plant. As Audrey Jr grows hungrier, it begins to demand food in a human voice (Charles B. Griffith). Frustrated, Seymour takes a walk at night and stops by the train tracks, chucking a rock in anger. To his horror, the rock hits a nearby man who falls onto the tracks and is run over by a speeding train. Seymour is terrified, but he collects the man's body parts and takes them back to the shop for Audrey Jr's dinner.
Mushnick and Audrey are celebrating she shop's sudden success at a fancy restaurant, when Mushnick realizes he had left his wallet at the shop. While Audrey waits at the table, Mushnick returns to work and sees Seymour feeding human meat to the plant. Seymour is not aware he was being watched, and a shaken Mushnick returns to the restaurant (without his wallet) and demands copious amounts of alcohol.
Mushnick considers going to the police and turning in Seymour, but decides against it to preserve the shop's steady business flow. Seymour arrives at work with a toothache, and Mushnick sends him to the local dentist, Dr. Farb (John Shaner), who is something of a sadist and attempts to pull several of Seymour's teeth. Seymour defends himself by attacking Farb with a sharp dental tool, eventually stabbing him to death. Horrified, Seymour arranges the body in the dentist's chair to resemble a patient, while he himself dons the dentist's uniform. An odd customer, Wilbur Force (Jack Nicholson), an extreme masochist who goes to the dentist for a pain fix, insists that Seymour (who he assumes is Dr. Farb) drill and pull his teeth. Seymour reluctantly agrees, and Force leaves happy. Seymour then collects Dr. Farb's body and brings it back to Audrey Jr.
Two police investigators, Joe Fink (Wally Campo) and Frank Stoolie (Jack Warford) arrive at the flower shop to investigate the two recent disappearances. Mushnick acts very nervously, but the men assume he knows nothing and leave. Seymour is becoming a local celebrity, and has worked up enough courage to ask Audrey on a date, which she gleefully accepts. A representative from the Society of Silent Flower Observers of Southern California visits the shop and admires Audrey Jr, who is now seven feet tall. The woman announces that her organization wants to award Seymour a trophy, which they will present the following night when the plant's large buds are scheduled to open.
Seymour and Audrey visit Winifred, who prepares a dinner solely consisting of different medicines. Mushnick stays at the shop, keeping close watch over the plant. Audrey Jr demands food, but Mushnick refuses to indulge it. Soon, a robber enters the store and threatens Mushnick at gunpoint for money. Disappointed by what he finds in the cash register, the robber demands to know where the rest of the loot is kept. Mushnick, attempting to kill two birds with one stone, lies to the robber and says that the rest of the money is hidden in the bottom of the huge plant. The robber climbs in to Audrey Jr's pod and is eaten. Audrey Jr quickly grows healthier.
Seymour becomes fed up with the plant, as it is damaging his relationship with Audrey. He angrily refuses to continue feeding it, but Audrey Jr verbally hypnotizes Seymour, sending him out with the singular goal of bringing back another victim. A dazed Seymour encounters a persistent call girl (Meri Welles) whom he knocks unconscious with a rock and hauls back to the shop for Audrey Jr's next meal.
The next evening, Seymour's trophy ceremony is underway. An audience, including Winifred and the two investigators, has assembled and waits eagerly for the plant's buds to open. As they do, the attendees are shocked to see a human face in each new flower, each belonging to one of the plant's meals: the man from the railroad tracks, Dr. Farb, the robber, and the call girl. In a panic, Seymour flees the shop and is pursued by Mushnick and the investigators who lose his trail when Seymour hides in a junkyard. He returns to the empty shop in a rage as Audrey Jr demands more food. Blaming the plant for ruining his life, Seymour grabs a knife and climbs into the plant in an attempt to kill it from the inside. When Mushnick and the others return, they see Audrey Jr has sent up a new flower; this one with Seymour's face.