Although desert dust aerosols affect more than half of the world's countries, the mechanisms of their oxidative toxicity have long been underrecognized. To break through this limitation, we conducted a comprehensive investigation of the oxidative potential (OP) and generation mechanisms of dust aerosols through multievent sampling across desert source regions (Taklamakan and Tengger deserts) and downwind areas, combined with independent laboratory simulations of surface sand emissions from these source regions. We reveal that desert dust exhibits OP comparable to that of urban aerosols, challenging the notion of low toxicity of desert dust. Typical OP drivers (organic components and metal ions) are insufficient to explain this elevated OP. We propose that mechanical processes such as saltation and sandblasting, which occur during dust entrainment, induce the formation of mineral free radicals on the PM surface-serving as an important source of reactive species that enhance OP. Furthermore, chemical processes such as photoaging contribute to enhanced OP in dust aerosols, explaining the contradiction that the dust aerosols observed in urban areas are essentially higher than those observed in desert areas and urban aerosols. This study fundamentally revises our understanding of desert dust toxicity, establishing its significant health risk as a major natural aerosol source.