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Crewed missions to the Moon may resume as early as 2026 with NASA's Artemis III mission, and lunar dust exposure/inhalation is a potentially serious health hazard that requires detailed study. Current dust exposure limits are based on Apollo‐era samples that spent decades in long‐term storage on Earth; their diminished reactivity may lead to underestimation of potential harm that could be caused by lunar dust exposure. In particular, lunar dust contains nanophase metallic iron grains, produced by “space weathering”; the reactivity of this unique component of lunar dust is not well understood. Herein, we employ a chemical reduction technique that exposes lunar simulants to heat and hydrogen gas to produce metallic iron particles on grain surfaces. We assess the capacity of these reduced lunar simulants to generate hydroxyl radical (OH*) when immersed in deionized (DI) water, simulated lung fluid (SLF), and artificial lysosomal fluid (ALF). Lunar simulant reduction produces surface‐adhered metallic iron “blebs” that resemble nanophase metallic iron particles found in lunar dust grains. Reduced samples generate ~5–100× greater concentrations of the oxidative OH* in DI water versus non‐reduced simulants, which we attribute to metallic iron. SLF and ALF appear to reduce measured OH*. The increase in observed OH* generation for reduced simulants implies high oxidative damage upon exposure to lunar dust. Low levels of OH* measured in SLF and ALF imply potential damage to proteins or quenching of OH* generation, respectively. Reduction of lunar dust simulants provides a quick cost‐effective approach to study dusty materials analogous to authentic lunar dust. [ABSTRACT FROM AUTHOR]