Millions of people have died due to coronavirus infection, which has also brought an unparalleled global health crisis to the verge of collapsing several nations healthcare system. The host genetic landscape is becoming more widely acknowledged as a crucial determinant of susceptibility to infection among all other factors. It is still unclear how exactly they are related, though. As a result, we looked into the significance of genetic factors in COVID-19 patients’ severity by performing a thorough analysis of research that were documented in the literature. A thorough search of PubMed was started at the beginning of July 2021. From December 2019 to July 2021, we retrieved all pertinent papers and screened on inclusion and exclusion criteria. This systematic review comprised twenty-five papers with COVID-19 case studies for qualitative synthesis. Seven different gene types, including human leukocyte antigen (HLA), angiotensin-converting enzyme 2 (ACE2), transmembrane serine protease 2 (TMPRSS2), ABO, Cluster of differentiation 45 (CD45), open reading frame (ORF) and interleukin-6 (IL-6) genes were identified, which might be responsible for the significance of coronavirus illness in the patients. Overall, individuals with COVID-19 who also possess the aforementioned genes are at a higher risk of developing significant illness. Still, more information is needed to draw a reliable conclusion.