In an Edinburgh graveyard in 1871, medical student Donald Fettes reassures a bereaved mother about the security of her little son's grave.  Soon after, Mrs. Marsh arrives at the house of Dr. Toddy MacFarlane, seeking a cure for her paralyzed daughter Georgina.  MacFarlane orders his student, Fettes, to examine the girl.  Although the doctor advises an operation, he refuses to perform the surgery, claiming that his teaching responsibilities preclude his practice of medicine.

Later, after Fettes discloses that he must give up his medical studies for lack of funds, the doctor offers him a job as his assistant.  In the lab that night, MacFarlane confides to Fettes that not all of the cadavers dissected by the students come from the morgue.  Later, Fettes is awakened by a pounding at the door, and finds John Gray, a cabdriver by day and grave robber by night, delivering the body of the little boy from the cemetery.  While strolling through town the next day, Fettes meets the boy's grieving mother, who is carrying the body of her son's guard dog from the cemetery.  Filled with remorse, Fettes tenders his resignation to MacFarlane, who refuses it on the grounds that human specimens are necessary for medical advancement.

At the inn that night, the doctor and his assistant are greeted by Gray, who begins to taunt MacFarlane.  When Fettes pleads Georgina's case, Gray challenges the doctor to operate, threatening to expose a dark secret if he refuses.  Later, when MacFarlane tries to renege on his promise by claiming that he has no spinal column on which to experiment before the surgery, Fettes visits Gray to ask him to procure another specimen.  Along the way, Fettes offers alms to a street singer and is horrified later that night when Gray appears at the lab carrying the singer's dead body.

The next morning, Fettes shows MacFarlane the body and accuses Gray of murder, a conversation overheard by Joseph, the doctor's assistant.  Warning Fettes that he could be arrested as an accomplice, MacFarlane advises him not to notify the police.  On the day of Georgina's surgery, Meg Cameron, MacFarlane's housekeeper and secret wife, comforts Mrs. Marsh through the agonizing procedure.

After Georgina's incision heals, however, the little girl is still unable to walk, and MacFarlane, tortured by his failure, goes to the inn to console himself with drink.  Gray finds him there and begins to torment the doctor with references to their shared dark past.  Upon returning to his stable that night, Gray is visited by Joseph, who demands money in exchange for his silence about the cabman's illicit activities.  Gray then tells Joseph the story of Burke and Hare, two infamous murderers who were hanged for procuring bodies for Dr. Knox, MacFarlane's mentor.  After completing his tale, Gray lurches forward and suffocates Joseph and then delivers his body to MacFarlane's lab as a "gift."

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As MacFarlane angrily goes to confront Gray, Meg recalls the trial of Burke and Hare in which Gray admitted to robbing graves to shield the real perpetrator, MacFarlane.  She then warns Fettes to leave immediately before he becomes another MacFarlane.  Meanwhile, MacFarlane visits Gray and offers him money to stop tormenting him.  When Gray vows that the doctor will never be rid of him, the two men struggle, and MacFarlane beats Gray to death.

The next day, Fettes meets Mrs. Marsh and Georgina at the ramparts.  As Fettes confides his disillusionment to Mrs. Marsh, Georgina hears the sound of a horse's hoof beats and stands to see the animal, proving that the operation was a success.  Rushing to the doctor's house to tell him the good news, Fettes is informed by Meg that MacFarlane is at the inn of a neighboring town, where he has gone to sell Gray's horse and carriage.  At the inn, Fettes is informed by MacFarlane about his plans to rob a freshly dug grave.

During a storm that night, MacFarlane unearths the coffin and loads the shrouded body into his carriage.  As they drive into the night, MacFarlane hears Gray calling to him and orders Fettes to stop the carriage and examine the body.  When Fettes steps out of the carriage and shines a light on the face of the corpse, MacFarlane thinks he sees Gray.  At that moment, the horses are spooked and run away, plunging the carriage and its occupants over a cliff.  Running to the wreck, Fettes observes MacFarlane's dead body with the corpse of a woman lying beside him.