Gabriel John Utterson, a lawyer, is on his weekly walk with his cousin, Richard Enfield. During that walk, they reach a door leading into a rather large house, and this motivates Enfield to tell Utterson of an encounter he had seen some months ago while coming home late at night between a man and a young girl. The man, a sinister figure named Edward Hyde, and a young girl, who has run to get a doctor, accidentally bump into one another, but Hyde proceeds to trample her. Enfield chases after Hyde, brings him back to the scene, and, after the doctor assures them that the girl is okay, though frightened, joins with the girl's family in forcing Hyde to pay £100 to avoid the scandal they will otherwise spread for his despicable behaviour. Hyde leads them to the building in front of which Enfield and Utterson have now paused, where he disappears, and re-emerges with £10 in gold and a cheque for the rest, drawn on the account of a reputable gentleman. (This gentleman is later revealed to be Dr. Henry Jekyll, one of Utterson's clients and old friends.) Jekyll had recently so draughted his will as to make Hyde the sole beneficiary in case of his death or—much to Utterson's disturbance—his disappearance for more than three months. This development concerns and disturbs Utterson, who makes an effort to seek out Hyde, fearing that Hyde is blackmailing Jekyll. When he finally sees Hyde, the latter's ugliness, as if deformed, amazes Utterson. Although Utterson cannot say exactly how or why, Hyde provokes an instinctive feeling of revulsion in him. Much to Utterson's surprise, Hyde willingly offers Utterson his address. After one of Jekyll's dinner parties, Utterson stays behind to discuss the matter of Hyde with Jekyll. This causes Jekyll to turn pale, which Utterson notices. Yet Jekyll assures Utterson that everything involving Hyde is in order and that Hyde should be left alone.
A year passes uneventfully. One night in late October, a servant girl witnesses Hyde beat a man to death with a heavy cane. The victim was MP Sir Danvers Carew, another of Utterson's clients, who was carrying a letter addressed to Utterson when he was killed. The police, who suspect Hyde, contact Utterson. He leads the officers to Hyde's apartment, feeling a sense of foreboding amid the eerie weather. (The morning is dark and wreathed in fog.) When they arrive at the apartment, the murderer has vanished, but they find half of the cane (described as being made of a strong wood but broken due to the beating) left behind a door. It is revealed to be one which Utterson himself gave to Jekyll. Shortly thereafter, Utterson again visits Jekyll, who now claims to have ended all relations with Hyde. Jekyll shows Utterson a note, allegedly written to Jekyll by Hyde, apologising for the trouble that he has caused him and saying goodbye. That night, however, Utterson's clerk, Mr. Guest, points out that Hyde's handwriting bears a remarkable similarity to Jekyll's own.
For two months, Jekyll reverts to his former friendly and sociable manner, as if a weight has been lifted from his shoulders. But in early January, Jekyll suddenly starts refusing visitors, and Dr. Hastie Lanyon, a mutual acquaintance of Jekyll and Utterson, dies suddenly of shock after receiving information relating to Jekyll. Before his death, Lanyon gives Utterson a letter, with instructions that he should only open it after Jekyll's death or his disappearance. In late February, Utterson goes out walking with Enfield, and they see Jekyll at a window of his laboratory. The three men start conversing, but a look of horror suddenly comes over Jekyll's face, and he slams the window and disappears. Soon afterwards, in early March, Jekyll's butler, Mr. Poole, visits Utterson in a state of desperation and explains that Jekyll has secluded himself in his laboratory for several weeks. Utterson and Poole travel to Jekyll's house through empty, windswept, sinister streets. Once there, they find the servants huddled together in fear. They go to see the laboratory where they hear that the voice coming from inside is not the voice of Jekyll and the footsteps are light and not the heavy footsteps of the doctor. After arguing for a time, the two of them resolve to break into Jekyll's laboratory.
Inside, they find the body of Hyde wearing Jekyll's clothes and apparently dead from suicide. They find also, as the second of three enclosures within a large envelope, a letter from Jekyll to Utterson promising to explain the entire mystery. (The first is a re-draughted will which disinherits Edward Hyde and names Gabriel John Utterson sole residuary legatee.) Utterson takes the document, the third enclosure, back to his home, where he first reads Lanyon's letter and then Jekyll's. The first reveals that Lanyon's deterioration and eventual death resulted from the shock of seeing Hyde drinking a serum (potion or "draught") and, as a result of doing so, turning into Dr. Jekyll. The second letter explains that Jekyll, having previously indulged unstated vices (and with it the fear that discovery would lead to his losing his social position) found a way to transform himself (writing of "the most racking pangs" accompanying this transformation) and thereby indulge his vices without fear of detection. But Jekyll's transformed personality, Hyde, was effectively a sociopath—evil, self-indulgent, and utterly uncaring to anyone but himself. Initially, Jekyll was able to control the transformations, but one night in August, he became Hyde involuntarily in his sleep.
At this point, Jekyll resolved to cease becoming Hyde. On the October night of Sir Danvers Carew's murder, however, the urge gripped him too strongly, and after the transformation he immediately rushed out and violently killed Sir Danvers. Horrified, Jekyll tried more adamantly to stop the transformations, and for a time he proved successful by engaging in philanthropic work. One day in early January, at a park, he considered how good a person that he had become as a result of his deeds in comparison to others, believing himself redeemed. However, before he completed his line of thought, he was seized by sensations of agony; once they had faded, he looked down at his hands and realised that he had suddenly transformed once again into Hyde. This was the first time that an involuntary metamorphosis had happened in waking hours. Far from the chemicals in his laboratory and now hunted by the police as a murderer, Hyde needed help to avoid being caught. He wrote to Lanyon (in Jekyll's hand), asking his friend to retrieve the contents of a cabinet in his laboratory and to meet him at midnight at Lanyon's home in Cavendish Square. In Lanyon's presence, Hyde mixed the chemicals, drank the draught, and transformed back into Jekyll. The shock of the sight, for which Lanyon condemned Jekyll and declared the two former friends irredeemably estranged, instigated Lanyon's deterioration and death. Meanwhile, Jekyll returned to his home, only to find himself ever more helpless and trapped as the transformations increased in frequency and necessitated even larger doses of the draught to reverse them. It was the onset of one of these spontaneous metamorphoses that caused Jekyll to slam his laboratory window shut in the middle of his conversation with Enfield and Utterson.
Eventually, one of the medicinal chemicals from which Jekyll had been preparing the draught ran low, and subsequent batches prepared by Jekyll from renewed stocks failed to produce the transformation. Jekyll speculated that the one essential ingredient that made the original draught work (a salt) must have itself been contaminated. After sending his butler Poole to one chemist after another, to purchase the salt that was running low, only to find it ineffective, he assumed that subsequent supplies all lacked the essential ingredient that made the draught successful for his experiments. His ability to change back from Hyde into Jekyll had slowly vanished in consequence. In March, as he inscribed his "confession," Jekyll wrote that even as he composed his letter, he knew that he would soon become Hyde permanently, having used the last of this salt and he wondered if Hyde would face execution for his crimes or choose to kill himself. Jekyll noted that, in either case, the end of his letter marked the end of the life of Dr. Jekyll. He ended the letter by saying, "I bring the life of that unhappy Henry Jekyll to an end." With these words, both the document and the novella come to a close.