Hydroxychloroquine (HCQ) is a conventional disease-modifying antirheumatic drug (DMARD), which is considered as relatively safe, and offers a modest efficacy profile for the treatment of inflammatory rheumatic diseases such as rheumatoid arthritis and systemic lupus erythematosus. In view of the anecdotal evidence on its immunomodulatory and anti-inflammatory properties, HCQ has been used as an off-label option in patients with osteoarthritis (OA), mainly for the treatment of inflammatory OA. Recently, many investigators have evaluated the safety and efficacy of HCQ for the treatment of OA in various randomized control trials (RCTs). While most RCTs have evaluated the HCQ in inflammatory OA (erosive hand OA), there are studies constituting knee OA patients as well. Currently, there are no systematic reviews that have summarized the evidence on the efficacy and safety of HCQ in OA population. Hence, this study aims to systematically review the evidence from RCTs assessing the efficacy and safety of HCQ for the treatment of OA. Biomedical databases such as PubMed, Embase, and Google Scholar will be searched to identify the RCTs of HCQ in patients with OA (hand, knee, hip, or any other OA). Cochrane risk of bias tool will be used to assess the quality of included studies. Review Manager 5 (Rev Man) and STATA Version 16 will be used to conduct the statistical analysis.