The inflammasome as a multiprotein complex has a role in activating ASC and caspase-1 resulting in activating IL-1β in various infections and diseases like corona virus infection in various tissues. It was shown that these tissues are affected by COVID-19 patients. According to the current evidence, melatonin is not veridical while possessing a high safety profile, however, it possesses indirect anti-viral actions owing to its anti-oxidation, anti-inflammation, and immune improving properties. This study aims to assess the impacts of melatonin as the complementary treatments on oxidative stress agents and inflammasome activation in patients with COVID-19. Melatonin supplement (9 mg daily, orally) was provided for the patients hospitalized with a COVID-19 analysis for 14 days. For measuring IL-10, IL-1β, and TNF-α cytokines and malondialdehyde (MDA), nitric oxide (NO), and superoxide dismutase (SOD) level and the expression of CASP1 and ASC genes, blood samples were gathered from the individuals at the start and termination of the therapy. Our findings indicated that melatonin is used as a complementary treatment to reduce the levels of TNF-α and IL-1β cytokines, MDA, and NO levels in COVID-19 patients and significantly increase SOD level, however, the levels of IL-10 cytokine possesses no considerable changes. The findings revealed that genes of CASP1 and ASC were dysregulated by melatonin regulating the inflammasome complex. Based on the findings of the current study, it is found that melatonin can be effective as a medicinal supplement in decreasing the inflammasome multiprotein complex and oxidative stress along with beneficial impacts on lung cytokine storm of COVID-19 patients.