The elderly are more prone to mortality from COVID-19 infection, as they are susceptible to develop acute respiratory distress syndrome (ARDS). For COVID-19 patients with ARDS caused by sepsis or septic shock, high-dose parenteral vitamin B12 appears to be a potential new treatment option. Vitamin B12 may play a substantial impact in COVID-19 morbidity and mortality reduction owing to its function in DNA synthesis, cellular control, improvement of anti-inflammatory immune responses, and decrease of pro-inflammatory responses. This review aims to assess the functional role of Vitamin B12 in COVID-19 in terms of its immunomodulatory effect, role in cellular and humoral immunity and maintaining the gut microbe homeostasis. From data inception to June 2021, accessible electronic databases were searched for research/review articles reporting on the function of Vitamin B12 in COVID-19. Scopus, Web of Science, PubMed, WHO worldwide research on COVID-19 and the clinical trials registration “https://clinicaltrials.gov/” were used to conduct the systematic search by using keywords: “COVID-19 and “Vitamin B12”. Also, based on these outcomes, it can be concluded that Vitamin B12 may have a potential role in preventing COVID-19 complications. Further, studies evaluating the role of Vitamin B12 in COVID-19 may open a new array of ideas on the optimal and the well-tolerated dose and timing of its administration in COVID-19 patients.