Background/Aims: Conventional disease-modifying anti-rheumatic drugs have been trialed in osteoarthritis (OA). Hydroxychloroquine (HCQ), which has shown its effectiveness in rheumatoid arthritis, has been trialed for the treatment of OA; however, its efficacy and safety remain unclear. This systematic review and meta-analysis evaluate efficacy and safety of HCQ for the treatment of OA. Methods: MEDLINE, EMBASE, and Cochrane Central were searched from inception through June 2020. Two reviewers independently screened for randomized controlled trials (RCTs) comparing HCQ with placebo or other active-comparators for the treatment of knee, hand, or hip OA, extracted data, and performed Cochrane risk of bias assessments. Results: Six RCTs, four in hand OA, two in knee OA, consisting of 842 patients (436 in HCQ arm, 406 in control arm) were included. RCTs were conducted between 2012 and 2020, one each at UK, Netherlands, Germany, Italy, Iran, and Egypt; follow-up period ranged 24 to 52 weeks. High-quality evidence showed no clinically important pain reduction with HCQ compared to placebo/active-control in hand OA (standardized mean difference [SMD], 0.14; 95% confidence interval [CI], –0.20 to 0.48). Effect on pain reduction in knee and hand OA was small and non-significant (SMD, –0.09; 95% CI, –0.44 to 0.25). High-quality evidence showed no improvement in dysfunction with HCQ compared to placebo in hand OA patients (SMD, 0.08; 95% CI, –0.23 to 0.40). Effect on dysfunction improvement in knee and hand OA was modest and statistically non-significant (SMD, –0.20; 95% CI,–0.57 to 0.18). No improvement in quality of life was observed in hand OA. Conclusions HCQ has no benefit in reducing pain and improving physical function in hand or knee OA patients.