AbstractHydrogen sulfide (H₂S) is a noxious, potentially poisonous, but necessary gas produced from sulfur metabolism in humans. In Down Syndrome (DS), the production of H₂S is elevated and associated with degraded mitochondrial function. Therefore, removing H₂S from the body as a stable oxide could be an approach to reducing the deleterious effects of H₂S in DS. In this report we describe the catalytic oxidation of hydrogen sulfide (H₂S) to polysulfides (HS_2+n⁻) and thiosulfate (S₂O₃²⁻) by poly(ethylene glycol) hydrophilic carbon clusters (PEG‐HCCs) and poly(ethylene glycol) oxidized activated charcoal (PEG‐OACs), examples of oxidized carbon nanozymes (OCNs). We show that OCNs oxidize H₂S to polysulfides and S₂O₃²⁻ in a dose‐dependent manner. The reaction is dependent on O₂ and the presence of quinone groups on the OCNs. In DS donor lymphocytes we found that OCNs increased polysulfide production, proliferation, and afforded protection against additional toxic levels of H₂S compared to untreated DS lymphocytes. Finally, in Dp16 and Ts65DN murine models of DS, we found that OCNs restored osteoclast differentiation. This new action suggests potential facile translation into the clinic for conditions involving excess H₂S exemplified by DS.