The novel coronavirus disease 2019 (COVID‐19), is currently the leading threat to public health and a huge challenge to the healthcare systems across the globe and caused by severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2). Obesity, a state of chronic inflammation, and diabetes mellitus are risk factors for severe SARS‐CoV‐2. Metformin is one of the most commonly used antidiabetic medications that displayed immunomodulatory activity through AMP-activated protein kinase. Metformin has sex-specific immunomodulatory and cytokine-reducing activities. Therefore, this review aimed to summarize the protective roles of Metformin and its possible molecular mechanisms for use in COVID-19 patients. To include studies, publications related to Metformin and its possible molecular mechanisms for COVID-19 were searched from the databases such as Web of Science, PubMed, Medline, Elsevier, Google Scholar, and SCOPUS, via English key terms. Maintaining proper blood glucose levels using oral antidiabetic drugs like Metformin reduced the detrimental effects of COVID-19 by different possible mechanisms such as Metformin-mediated anti-inflammatory and immunomodulatory activities; effect on viral entry and ACE2 stability; inhibition of virus infection; alters virus survival and endosomal pH; mTOR inhibition; and influence on gut microbiota. Fascinatingly, in diabetic patients with COVID-19, treatment with Metformin was associated with a noticeable reduction in mortality rates and disease severity among infected patients. Metformin was comprehensively investigated for its anti-inflammatory, antiviral capabilities, immunomodulatory, and antioxidant, which would elucidate its capability to confer vascular and cardiopulmonary protection in COVID-19.
