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This study investigated the therapeutic potential of a manganese dioxide-polymer dot (MnO2-PD)-incorporated hydrogel, designated as M-PD hydrogel, for modulating reactive oxygen species (ROS) within the osteoarthritis (OA) environment. Our research highlights the ability of the hydrogel to scavenge ROS, thereby influencing the differentiation of osteoclasts and protecting chondrocytes, offering a novel approach to osteoarthritis (OA) management. Our results indicated that the M-PD hydrogel increased electrical resistance and fluorescence recovery in the presence of osteoclasts, correlating with decreased ROS levels and suppressed expression of osteoclast differentiation markers. Coculture experiments revealed the protective effects of the hydrogel on chondrocytes by reducing the expression of matrix-degrading enzymes. In vivo application in burr holes and/or OA-induced mice revealed a significant reduction in osteoclast formation and cartilage destruction, suggesting the dual therapeutic action of the hydrogel in altering the joint microenvironment. These findings highlight the potential of targeting ROS in osteoclasts as a comprehensive therapeutic approach, offering not only symptomatic relief but also targeting the underlying mechanisms of disease progression in OA.