Aim: Many concerns still existed about the safety of hydroxychloroquine (HCQ) in the treatment of Corona Virus Disease 2019 (COVID-19). The purpose of this study was to evaluate the safety of HCQ by performing a systematic review and meta-analysis. Methods: Randomized controlled trials reporting the safety of HCQ in PubMed, Embase, and Cochrane Library were retrieved from the establishment of the database to February 27, 2020. Literature screening, data extraction, and assessment of risk bias were performed independently by two reviewers. Results: We identified 34 eligible studies that involved 3,639 patients. The difference in the cumulative number of AEs between the HCQ and control group was statistically significant (P<0.0001). The pooled incidence of gastrointestinal AEs, which occurred most frequently in the HCQ group was higher than that in the control group (P<0.0001) according to the system organ class. In addition, the risks of skin and subcutaneous tissue AEs (P = 0.011), renal and urinary disorders (P=0.011), ear and labyrinth AEs (P = 0.045) and surgical and medical procedures AEs (P = 0.020) in HCQ group are also significantly increased compared with the control group. Meanwhile, the cumulative number of SAEs was similar between the two groups (P=0.222). Meta-analysis results indicated that the pooled incidences of all the AEs reported by two or more studies were similar except for the treatment discontinuation caused by AEs (RD 0.02, 95% CI: 0.00 to 0.06). Conclusion: HCQ was well tolerated and might be safe for clinical application under the outbreak of COVID-19.