Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a member of the Coronaviridae family that causes the novel coronavirus disease (COVID-19). SARS-CoV-2 is an RNA enveloped virus that firstly emerged in Wuhan, China, in December 2019 over the 21st century. It is rapidly spread by human-to-human transmission through droplets or airborne particles. COVID-19 can be complicated by acute respiratory distress syndrome (ARDS) and severe pneumonia, depending on ACE2 and Spike protein (as viral surface protein). It is required a proper defense mechanism for the body to be healthy in fighting back against infectious diseases, especially COVID-19. Since there are no wholly approved drugs, vaccines, or clinical prevention for this disease at the moment, it is essential to focus on natural resistance systems, which play critical roles in supporting the immune system defense function against COVID-19. The severity of COVID-19 is characterized by an increase in acute phase reactants and pro-inflammatory cytokines; ferritin, tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and IL-1β. Numerous shreds of evidence propose that immune homeostasis, genetic susceptibility, dietary interventions, supplementation, and the environment can have an imperative role in controlling the severity of SARS-CoV-2 infection and infected patients’ prognosis. In the current study, we proposed a comprehensive overview of the considerable part of natural resistance in the COVID-19 forecast, whether it may afford protection to COVID-19. All in all, multidisciplinary investigations have been done and need to be done to identify the clinical implications of natural interventions and natural resistance potential in COVID-19 susceptibility