Vitiligo is an autoimmune skin disorder caused by dysfunctional pigment-producing melanocytes which are attacked by immune cells. Oxidative stress is considered to play a crucial role in activating consequent autoimmune responses related to vitiligo. Melanin synthesis by melanocytes is the main intracellular stressor, producing reactive oxygen species (ROS). Under normal physiological conditions, the antioxidative nuclear factor erythroid 2-related factor 2 (Nrf2) pathway functions as a crucial mediator for cells to resist oxidative stress. In pathological situations, such as with antioxidant defects or under inflammation, ROS accumulate and cause cell damage. Herein, we summarize events at the cellular level under excessive ROS in vitiligo and highlight exposure to melanocyte-specific antigens that trigger immune responses. Such responses lead to functional impairment and the death of melanocytes, which sequentially increase melanocyte cytotoxicity through both innate and adaptive immunity. This report provides new perspectives and advances our understanding of interrelationships between oxidative stress and autoimmunity in the pathogenesis of vitiligo. We describe progress with targeted antioxidant therapy, with the aim of providing potential therapeutic approaches.