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Melatonin is a neurohormone well-known as sleep disorder treatment. A few clinical trials have recently pointed out the biological plausibility of utilising melatonin in the treatment of coronavirus disease 2019 (COVID-19, SARS-CoV-2) patients. Melatonin wide range of activities include anti-inflammatory, antiviral and antioxidant effects. Our meta-analysis aimed to investigate the effect of melatonin on mortality in COVID19 patients with different disease severity. We searched PubMed, EMBASE, Web of Science with no language restrictions updated on February 2023 for randomized and propensity matched studies, comparing melatonin plus standard COVID-19 therapy vs. standard COVID-19 therapy alone. Patients had to be hospitalised with a confirmed diagnosis of SARS-CoV-2 infection. Primary outcome was mortality at the longest follow-up available. We included 7 randomized and 1 propensity matched studies enrolling 1155 overall patients with a mean age of 61 ± 19.5 years. We found a reduced mortality rate in the overall population (127/575 (22%) vs. 209/580 (36%) Relative Risk: 0.62 (confidence interval (CI): 0.40, 0.96), I2 = 86% p = 0.03, with the results confirmed when pooling the 5 studies which administered melatonin in non-intensivecare-unit patients (26/423 (6.1%) vs. 69/419 (16%) Relative Risk 0.30 (CI: 0.10, 0.86), I 2 = 40% p = 0.02). According to recent randomized and propensity matched evidence, melatonin might be a life-saving adjuvant therapy in COVID-19 patients. This effect was mainly driven by non-intensive care unit patients. [ABSTRACT FROM AUTHOR]