<p>With the ongoing global burden of COVID-19, identifying reliable biomarkers to predict disease severity remains a clinical priority. Melatonin, a hormone with immunomodulatory and antioxidant properties, has garnered attention for its potential role in regulating inflammation during viral infections. However, the relationship between serum melatonin levels and COVID-19 severity remains poorly understood. This study aimed to evaluate the correlation between serum melatonin concentration and COVID-19 severity to identify potential prognostic biomarkers. A cohort study was conducted, including patients diagnosed with COVID-19 between June 2020 and July 2022. Serum melatonin levels in patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2) were measured and analyzed in relation to disease severity and oxygen requirements. In addition, serum melatonin level between survivors and non-survivors were also compared in this study. Patients not requiring oxygen therapy exhibited significantly higher serum melatonin levels (45.09 pg/mL) compared to those requiring intensive oxygen therapy (32.17 pg/mL) (<i>p</i> &lt; 0.0001). Median serum melatonin levels were 41.57 pg/mL in survivors and 24.79 pg/mL in non-survivors (<i>p</i> = 0.0005). In addition, non-survivors with symptoms such as respiratory distress and stress displayed lower serum melatonin compared to survivors (<i>p</i> = 0.0022). Serum melatonin concentration at admission was found to be significantly lower in patients with critical or fatal COVID-19, suggesting that serum melatonin levels may serve as a potential biomarker for disease severity.</p>