Severe acute respiratory syndrome CoV-2 (SARS-CoV-2) caused the global coronavirus disease 2019 (COVID-19) pandemic, which adversely affected almost all aspects of human life and resulted in the loss of millions of lives, while affecting nearly 0.67 billion people worldwide. SARS-CoV-2 still poses a challenge to the healthcare system as there are more than 200,000 active cases of COVID-19 around the globe. Epidemiological data suggests that the magnitude of morbidity and mortality due to COVID-19 was low in a few geographical regions and was unpredictably higher in a few regions. The genetic diversity of different geographical regions might explain the sporadic prevalence of the disease. In this context, human leukocyte antigens (HLA) represent the most polymorphic gene-dense region of the human genome and serve as an excellent mini-genome model for evaluating population genetic diversity in the context of susceptibility and progression of various diseases. In this review, we highlight the plausible influence of HLA in susceptibility, severity, immune response, and designing of epitope-based vaccines for COVID-19. Further, there is a need for extensive investigations for illustration and clarification of the functional impact of HLA class I and II alleles in the pathogenesis and progression of SARS-CoV-2.