Background: Drug resistance in cancer is steadily rising, making the development of new therapeutic targets increasingly critical for improving treatment outcomes. Purpose: The mutual regulation of ions is essential for cell growth. Based on this concept, ion interference strategies offer a highly effective approach for cancer treatment. Calcium ions (Ca), as major second messengers, are closely associated with ion exchange and homeostasis. Disruptions in this balance can lead to cell death. However, while iron ions are also crucial, the connection between Caand iron-induced cell death (ferroptosis) has not been well established. Therefore, this study suggests that Ca may play a role in the induction of ferroptosis, presenting a novel and efficient target for cancer therapy. Study Design: PubMed, Google Scholar, and Web of Science databases were systematically searched for articles published in the past 15 years on the mechanisms of calcium ion-induced ferroptosis in cancer and related drugs. Results: The analysis highlights how Caregulate ferroptosis. The mechanisms by which Cainfluence ferroptosis are summarized based on existing literature, and relevant drugs that act on Ca/ferroptosis axis are outlined. Conclusion: Ca regulate ferroptosis primarily through the modulation of reactive oxygen species (ROS) and glutathione (GSH) levels, a mechanism that applies to a wide range of cancer cells as well as paracancerous and normal cells in cancer treatment. Furthermore, plant-derived active compounds exhibit potent anticancer properties and often act on the Ca/ferroptosis axis. These natural compounds could play a significant role in the development of new cancer treatment strategies.