Ferroptosis is a programmed cell death, and its mechanism involves multiple metabolic pathways, such as iron and lipid metabolism, and redox homeostasis. Exerkines are important mediators that optimize cellular homeostasis and maintain physiological health during exercise stimulation. This article comprehensively examines the mechanisms and regulatory networks for governing ferroptosis and summarizes the impact of exercise and exerkines on ferroptosis under varying load intensities and disease contexts. Notably, despite its significant efficacy and minimal side effects, the therapeutic and prognostic potential of exercise in ferroptosis-related diseases remains largely unexplored. This article, by summarizing recent progresses in the regulation of exerkines-mediated ferroptosis, could further uncover the preventive or alleviative mechanisms of some diseases upon exercise interventions, which will be beneficial to design exercise interventional strategies for alleviating disease progression through the regulation of ferroptosis.