<p>Ferroptosis, a novel form of programmed cell death, is closely linked to the imbalance between cellular oxidative stress and antioxidant defenses. Studies have shown that the occurrence and progression of ferroptosis are associated with Nrf2 and ROS levels, providing important guidance for ferroptosis research and the development of novel therapeutic strategies targeting Nrf2/ROS-related mechanisms. Despite its potential in treating various diseases, the clinical application of ferroptosis modulation is limited due to an insufficient interventional strategy and mechanism. Sestrin proteins are highly conserved family proteins induced by stress and injury. They function in mTORC regulation, ROS inhibition, and leucine binding. Emerging direct evidences suggest sestrin proteins inhibit ferroptosis in various pathological contexts, and numerous studies of sestrin proteins and Nrf2/ROS (the core to ferroptosis) have provided a series of indirect evidence that sestrin proteins and ferroptosis are strongly correlated. In the present study, the regulatory effects of sestrin proteins on ferroptosis/Nrf2/ROS were reviewed to describe the interplay between sestrin proteins and ferroptosis, alongside exploring their potential mechanisms. The present study represents the first comprehensive review dedicated to examining the relationship between ferroptosis and sestrin proteins. This work offers clinicians and researchers a thorough framework for assessing the dynamics of ferroptosis and sestrin proteins.</p>