Yi San dramatizes the life of Korea's King Jeongjo, the 22nd ruler of the Joseon Dynasty. Jeongjo is remembered in Korean history for his sympathy with the plight of the common man, in spite of his own pampered upbringing as royalty. The drama begins with the King's early years, during which he befriends two children working in the Palace who are later expelled. King Yeongjo (Jeongjo's grandfather) seals Jeongjo's father, Crown Prince Sado, in a rice storage chest with no food or water because he fears that the crown prince is planning a coup. Jeongjo wants to save his father, and with the help of his friends Seong Song Yeon and Park Dae Su, begs King Yeongjo to forgive the Crown Prince.
The drama then skips forward to Jeongjo's adult years when he and his friends re-establish contact with each other. Throughout, Jeongjo's position as Crown Prince is threatened by palace intrigues. The Crown Prince, Jeongjo, begins to fall in love with one of his childhood friends, Seong Song Yeon, whose father, a palace artist, died when she was young. The story then follows Yi San's rise to power, his assumption of the kingship, and the labyrinthine palace intrigues that he must constantly guard against from the No-ron Faction. While the show does deviate from the historical record in a number of ways, its representation of court life during the Joseon Dynasty appears to be based on contemporary sources.