Conventional pharmacotherapy exhibits limited efficacy in halting cartilage degeneration, whereas exercise interventions have demonstrated promising protective effects against osteoarthritis (OA), albeit with unclear underlying mechanisms. This study investigated the beneficial effects of swimming in mitigating local joint damage through the enhancement of systemic antioxidant capacity. We found that overexpression of superoxide dismutase 3 (SOD3) could promote the elimination of extracellular reactive oxygen species (ROS) and preserve the cartilage extracellular matrix (C-ECM). Conversely, genetic deletion of SOD3 accelerated the loss of C-ECM and contributed to OA due to an imbalance in extracellular oxidative stress. Further investigation revealed that SOD3 could interact with CCAAT/enhancer binding protein β (C/EBPβ), leading to the inhibition of apolipoprotein E (APOE) transcription and subsequent APOE-induced cholesterol transport. Ultimately, we developed targeted extracellular vesicles (EVs) with high cartilage affinity for efficient and precise delivery of SOD3. Overall, this study elucidated the potential of exercise for degenerative joint disorders through SOD3-mediated extracellular antioxidation and cholesterol redistribution.