The One and Only is a human melodrama that follows the lives of three terminally ill women who meet at a hospice ward. Pyo In-sook, a woman diagnosed with a terminal illness, finds her life intertwined with Kang Se-yeon and Seong Mi-do. Feeling that they have nothing left to lose, they decide to kill one 'bad guy' before their time runs out. However, their plan takes an unexpected turn when they encounter Min Woo-cheon, a mysterious man living a dark and difficult life. As the women navigate their final days, the series explores themes of grief, redemption, and the profound impact of human connection. The narrative shifts from a crime-thriller premise into a poignant character study, focusing on how these individuals find meaning and love in the face of inevitable death. The investigation into the murder case serves as a backdrop for the evolving relationships and the search for the 'one and only' person who truly matters.