Doctor Tom Jackman is a married father of two. A psychiatric nurse named Katherine Reimer takes a job caring for him. Abandoned by his mother as a child, Jackman has split from his wife, Claire. In the first episode, Jackman straps himself into a chair and Reimer watches as he undergoes a subtle physical transformation. While Hyde and Jackman are physically nearly identical, a running element of the series is the way in which others perceive them as distinct to the point of asking one where the other has gone.
Reimer observes that Jackman's alter ego exhibits rage, heightened senses, greatly superior strength and speed, and a more playful and flirtatious manner. She assures this persona she will keep his secrets just as she keeps Jackman's, but asks for guarantees he will not harm her. After being informed of the case of Dr. Jekyll and Mr. Hyde, Hyde takes the titular alter ego's name for his own and the two agree to respect the other's autonomy.
Jackman transforms after visiting his family, from whom he has kept his Hyde persona a secret. To Jackman's family he becomes 'Uncle Billy', Jackman's long-lost cousin. This begins the escalation of conflict between Jackman and Hyde, with both leaving notes for the other before transforming.
Miranda Callendar, a detective employed by Claire, learns about Hyde and informs Jackman that Jekyll and Hyde was not fiction, but a fictionalized version of actual events. There was a Doctor Jekyll who lived in Edinburgh. When he is shown a picture of Jekyll, Jackman realizes he looks exactly like him. He assumes he is a descendant of Jekyll's, but Callendar informs him Jekyll died without children.
Jackman's friend Peter Syme (who is his boss at the biotech firm of Klein and Utterson) and an American named Benjamin are revealed to belong to a group which has been tracking Jackman/Hyde. He meets a woman who claims to be his mother and who has been working with Reimer, but learns no more from her before she leaves. Jackman heads to Syme's house to learn the truth. Syme attempts to drug him, informing him that Benjamin and other personnel from Klein and Utterson are on their way. Feeling Hyde taking over, Jackman locks himself and Syme in the house's basement, not realizing Claire has been in the house and is also hiding in the basement. After toying with Syme and Claire, Hyde is confronted by the men from Klein and Utterson. Hyde is captured, but first kills Benjamin. Claire argues they need to find a cure for him. Syme informs her they have a cure and Claire watches, bound and gagged, as her husband is locked in a metal coffin.
Reimer and Callendar confront Syme, claiming they know the truth about Jackman. Callendar says Klein and Utterson have access to cloning technology and that Jackman is Jekyll's clone. Syme denies this and orders them taken away. He reveals to Claire the "cure" her husband is undergoing will purge Jackman's persona, not Hyde. Klein and Utterson want to examine Hyde in order to synthesize the potion that turned the original Jekyll into Hyde. When the box is opened, Hyde is dominant. In a flashback triggered by genetic memory, Hyde sees a meeting between Jekyll and Robert Louis Stevenson, the author of the Strange Case of Dr Jekyll and Mr Hyde. Stevenson reveals that he knows, "there is no potion." Jekyll lied to trap anyone who might try to create another Hyde. Jackman also learns there was a maid in Jekyll's household whom he was in love with and looks like Claire. It was the love for this woman that released Hyde. Hyde manifests, exhibiting greater superhuman abilities (including a limited ability to control electricity) and cuts his way through the Klein and Utterson personnel.
Enraged by further attempts to harm their family, Jackman and Hyde escape from Klein and Utterson. But Mrs Utterson takes Claire and her sons prisoner, trapping the boys in boxes similar to that which had been used on Jackman. Managing to make her way into the lowest level of Klein Utterson Claire encounters Jackman's mother. She explains to Claire that while although Jekyll had no descendants, Hyde did. She also explains that Klein Utterson did attempt to clone Jekyll but never managed to do it successfully. They did, however, manage to clone that which served as the catalyst to release Hyde. Claire is a clone of Alice, Jekyll's maid. Eventually, Hyde appears and in a confrontation with Mrs Utterson he sacrifices himself to save Jackman's family.
Six months later Jackman, apparently free of Hyde, has tracked down his mother. Confronting her he asks about his origins, asserting that he couldn't possibly be descended from Jekyll. She tells him that she is not the descendant of Jekyll, but rather a descendant of Edward Hyde. The final shot of the series is of Jackman's mother transforming into her own Hyde persona, that of Mrs. Utterson.