Age-related macular degeneration (AMD) is a complicated disease that causes irreversible visual impairment. Increasing evidences pointed retinal pigment epithelia (RPE) cells as the decisive cell involved in the progress of AMD, and the function of anti-oxidant capacity of PRE plays a fundamental physiological role. Nuclear factor erythroid 2 related factor 2 (Nrf2) is a significant transcription factor in the cellular anti-oxidant system as it regulates the expression of multiple anti-oxidative genes. Its functions of protecting RPE cells against oxidative stress (OS) and ensuing physiological changes, including inflammation, mitochondrial damage and autophagy dysregulation, have already been elucidated. Understanding the roles of upstream regulators of Nrf2 could provide further insight to the OS-mediated AMD pathogenesis. For the first time, this review summarized the reported upstream regulators of Nrf2 in AMD pathogenesis, including proteins and miRNAs, and their underlying molecular mechanisms, which may help to find potential targets via regulating the Nrf2 pathway in the future research and further discuss the existing Nrf2 regulators proved to be beneficial in preventing AMD.