Cell death is a crucial mechanism through which cells respond to damage and stress, thereby maintaining homeostasis. Cell death pathways include both caspase-dependent and caspase-independent mechanisms, such as apoptosis, necrosis, autophagy, and ferroptosis. The recent discovery of oxeiptosis identifies a unique form of ROS-mediated, caspase-independent cell death with apoptotic-like features. This process is regulated by key molecules, including KEAP1, PGAM5, and AIFM1, and is characterized by distinct molecular and morphological features. These regulators contribute to cellular integrity by activating cytoprotective genes through Nrf2 stabilization by KEAP1 and maintaining cellular homeostasis via PGAM5-mediated AIFM1 Ser116 dephosphorylation. In this review, we discuss the broad spectrum of oxeiptosis-mediated regulation in disease pathogenesis by combating ROS-induced cellular damage. Modulating oxeiptosis helps in disease management by mitigating ROS-induced cellular damage, restoring redox balance, and preventing pathological inflammation. Additionally, we highlight modulators such as natural derivatives and lncRNAs that trigger oxeiptosis in various diseases, including vitiligo, psoriasis, and multiple cancer types. Modulating oxeiptosis presents significant clinical implications by offering novel therapeutic strategies to mitigate oxidative stress, restore cellular homeostasis, and prevent inflammation-driven diseases. This review emphasizes potential therapeutic advances for conditions characterized by aberrant ROS accumulation, offering innovative avenues for clinical intervention and treatment development.