Tendinopathy is a degenerative disease characterized by rupture, pain or loss of strength at tendon tissues. Multiple intrinsic and extrinsic factors, such as aging and fluoroquinolones, are involved in the development of tendinopathy. However, despite much work, the exact pathophysiological mechanism remains unclear. In this study, we analyzed databases of self-reported adverse events and IBM MarketScan insurance claims database to explore a coexisting drug that reduced the incidence of tendinopathy, and found that dexamethasone prevented fluoroquinolone-induced tendinopathy. In experimental validation of the hypothesis, chronic treatment of pefloxacin to rats caused mechanical fragility and histological changes in tendon, which were both mitigated by the cotreatment of dexamethasone. For its molecular mechanism, in vitro studies revealed that oxidative stress was increased in pefloxacin-treated tenocytes, which was suppressed with the cotreatment of dexamethasone. Also, the increase in the gene expression level of glutathione peroxidase 3 (GPX3) was observed in dexamethasone-treated tenocytes. In fact, the overexpression of GPX3 mitigated pefloxacin-induced oxidative stress in tenocytes. These results suggest that dexamethasone reduces risk of tendinopathy by suppressing oxidative stress through the upregulation of GPX3. This data-driven approach based on clinical evidence will pave the way for the identification of therapeutic target for tendinopathy with high clinical predictability.