The story is set in Korea during the reigns of King Seongjong, King Yeonsan-gun (1494-1506) and King Jungjong (1506-1544). The story begins with Queen Yun, mother of King Yeonsan-gun (the Crown Prince at the time) being poisoned by a group of imperial guards under the order of the king.
After the incident, an imperial guard, Seo Cheon-soo, who accompanied the group, suffers an accident on his way home. He is rescued by an enigmatic hermit, who tells him that his life will revolve around three women: he doesn't want to kill her but she still died because of him, he will save the life of the second woman but she will die because of him, and a third woman who will kill him, but who will be the savior of many lives. (It does not become clear until much later that the three women are Lady Yun (Yeonsangun's mother), Park Myeong-yi (Jang-geum's mother), and lastly, Jang-geum herself.). Psychological distress from the incident eventually caused him to resign. Palace cook Park, an apprentice at the Royal Kitchen, witnesses a conspiracy against the Queen Mother by Lady Choi and Park Myeong-yi is in turn indicted on false charges by the inner circle of senior kitchen staff, and secretly executed by their internal procedures (forced to drink poison). She is first saved by Palace cook Han, her best friend in the palace, who mixes antidote with the poison and slips her a letter, and was later on saved, inadvertently by the retired Seo. The two married and secretly lived in a remote village as low class people cheonmin, raising a very bright young daughter, Seo Jang-geum.
In the year 1504, King Yeonsangun orders a massive investigation into his mother's murder, and eventually finds Seo and his family, partly because Jang-geum blurted out the truth that her parents were not low-class people, that Seo was a military officer of the palace. This leads to the arrest of Seo and the scattering of their family. Jang-geum and her mother fled, but her mother was fatally wounded by their enemies. Before her death, she tells Jang-geum her last wish, that she to become the Head Lady of the Royal Kitchen and record the injustice done to her, in the Head Kitchen Ladies' journal or record book.
Jang-geum manages to enter the palace. Through her courage, curiosity, talent, kind-heartedness and determination, she helps Lady Han (her mother's best friend, which she does not discover until much later) to become the Highest Kitchen Lady. She undergoes many ordeals and is shunned because she is smarter than the other apprentices. Jang-geum continues cooking with the philosophy that the goal of cooking is to bring good health and happiness to the person who eats the food. A conspiracy headed by Lady Choi and her niece Geum-yeong, as well as high-rank officials and merchant Pan-sul Choi (Lady Choi's brother) to retain monopoly over Royal Kitchen supplies, results in the exile of Lady Han and Jang-geum to Jeju Island as slaves, on false accusations of treason. On the way to Jeju, an exhausted Lady Han dies. Lady Choi replaces her as the Highest Kitchen Lady.
While Jang-geum is on Jeju Island, she meets Jang-deok, whom she believed was a fellow slave. She soon discovers that Jang-deok is a famous Medical woman. Jang-deok's frank and pragmatic nature initially offends her, but she learns that she is dedicated to saving lives. Jang-geum learns that competent medical women can work in the Palace through a vigorous selection process. She realizes that is the only way she can return to the palace to avenge her mother and Lady Han. Under Jang-deok, she learns medicine, and her hard work and tenacity makes her a competent medical woman. In her quest to become a medical woman, she must rid herself of the hatred in her heart to truly embrace the virtues of being a medical practitioner. This she does, and re-enters the palace.
She comes face to face with Geum-yeong, who has now become the Head Kitchen Lady. Her predecessor, the ruthless Lady Choi, has become Head Lady, after kicking out the previous Lady Park. As they plot to rid themselves of her once and for all, Jang Geum's relationship with Lt. Min Jeung-ho (who is now part of the King's royal cabinet) intensifies. Jang-geum's best friend, Yeon-seng, has become the king's concubine while Jang-geum has been away and becomes the eighth Queen. Jang Geum correctly diagnosed that the King was suffering from Behçet's disease and not from typhoid fever. Through a dramatic interrogation process, the past plots of Lady Choi and her subordinates are revealed, resulting in the destruction of the Choi family and high-ranking officials.
Through her dedication to the royal family, perseverance and skill, she was recognised as the best medical person in the palace. Jang-Geum had correctly diagnosed the Queen as having a second stillborn fetus in her womb, saving her life. She convinced the Queen Mother to undergo medical treatment and discovered the root cause of the King's chronic illness. She earns the gratitude of the Queen, when she cures the prince of small pox.
The King falls in love with Jang-Geum, but refrains from making her a royal concubine because he understands that Jang-Geum's loves medicine. In recognition of her achievements and to keep her by his side, the King makes her his personal physician, conferring on her the use of "Dae" (meaning "The Great") and the position of a third rank official in a 9-rank system (where the lowest-ranking official is the ninth-rank official).
The King's decision is met with much outcry from scholars and ministers, since having a woman in the elite bureaucracy was an open defiance of the country's precedent and having a medical woman as the King's personal physician was unheard of. Jang-Geum, understanding that she could assert the rights and capability of women by accepting the post, reluctantly does so. Jeung-ho, in his staunch support of her promotion, is indicted for going against scholarly teachings and exiled. They are thus separated.
The King became critically ill and there was little Jang-geum could do, despite her comprehensive understanding of his condition and attentive care. He could no longer be treated with acupuncture or medicine. As a last resort, she suggested surgery. The court officials were horrified at her revolutionary approach, which was unheard of and moreover, the King was considered too sacred to be allowed to bleed. Though the King believed in her, he was concerned that should the surgery fail, Jang-geum would surely be put to death. With his condition deteriorating, the King knew his end was near, but he was more worried about Jang-geum's fate. To protect her, the King sent her away against her wishes, allowing her to reunite with Jeong-ho and escape the palace. They married and live together for eight years with their daughter. All this while, Jang-geum and Jeong-ho are compelled to lead vagrant lives, as their detractors have been searching for them since King Junjong's death. However, Jang-geum continues to treat patients wherever she goes.
As a result, they were finally traced down and returned to the palace. Instead of being punished, both were reinstated by the Queen Dowager - formerly Queen Munjeong who favoured Jang-geum when she was a medical woman, and now wields enormous power. Jang-geum finds that all her friends have high ranks in the palace, making the palace much more peaceful than under Choi rule. Jang-geum and Jung-ho are wary of palace politics and decide to move on. The story ends as Jang-geum performs the first caesarean surgery in Korea.