Background: Coronavirus Disease MESHD 2019 (COVID-19) has become a major global issue with rising the number of infected individuals and mortality in recent months. Among all therapeutic approaches, arguments have raised about hydroxychloroquine (HCQ) efficacy in the treatment of COVID-19. We carried out a systematic review and meta-analysis overcome the controversies regarding the effectiveness of hydroxychloroquine in the treatment of COVID-19. Methods: A systematic search was performed in PubMed, Scopus, Embase, Cochrane Library, Web of Science, Google Scholar and medRxiv pre-print database using all available MeSH terms for COVID-19 and hydroxychloroquine up to July 19, 2020. Studies focused on the effectiveness of HCQ with/without azithromycin (AZM) in confirmed COVID-19 patients were entered into the study. Two researchers have independently evaluated quality assessment of the studies and abstracted data for data extraction. Extracted data were analyzed using CMA v. 2.2.064. Heterogeneity was assessed using the I-squared (I2) test, and fixed/random-effects model was used when appropriate for pooling of studies. Results: Out of 26 studies entered into our systematic review, 21 studies including 14 comparative studies with control group and seven observational studies containing 103,486 participants have entered into the meta-analysis. The results of the meta-analysis on comparative studies indicated no significant clinical effectiveness (negative in RT-PCR evaluation) for HCQ regimen in the treatment of COVID-19 in comparison to control group (RR: 1.03, 95% CI, 0.79-1.34). The same result was observed for the combination of HCQ+azithromycin (RR: 1.26, 95% CI, 0.91-1.74). No significant differences were found for both HCQ (RR: 0.92, 95% CI, 0.72-1.16) and HCQ+AZM (RR: 1.72, 95% CI, 0.86-3.42) mortality rate; however, mortality was affected by age TRANS differences according to meta-regression analysis (P<0.000001). No substantial difference was observed for disease MESHD exacerbation (RR: 1.23, 95% CI, 0.65-2.30) between HCQ group and controls. Also, radiological findings significantly improved in the HCQ group (OR: 0.32, 95% CI, 0.11-0.98). Odds of known HCQ adverse effects ( diarrhea MESHD diarrhea HP, vomiting MESHD vomiting HP, blurred vision HP, rash, headache MESHD headache HP, etc.) occurred in the HCQ regimen group was approximately 3.5 times of control group (OR: 3.40, 95% CI, 1.65-6.98), but no substantial differences were found regarding intubation odds between HCQ group and control group (OR: 2.11, 95% CI, 0.31-14.03). Meta-analysis indicated no significant prophylactic effects for HCQ (OR: 0.40, 95% CI, 0.04-3.65) Conclusion: This systematic review and meta-analysis showed no clinical benefits regarding HCQ treatment with/without azithromycin for COVID-19 patients. Although mortality rate was not significantly different between cases and controls, frequency of adverse effects was substantially higher in HCQ regimen group. However, due to that most of the studies were non-randomized and results were not homogenous, selection bias was unavoidable and further large randomized clinical trials following comprehensive meta-analysis should be taken into account in order to achieve more reliable findings. Also, it is worth mentioning that if this work does not allow to quantify a "value" of the HCQ, it allows at least to know what is not the HCQ and that it would be prudent not to continue investing in this direction.