The COVID-19 pandemic caused by the novel Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2) has posed a unique threat to global clinical and research scenarios and economies. Beyond the direct effects of the virus, understanding how it interacts with the host’s genetic and epigenetic machinery is crucial for developing effective treatments. Understanding the interplay between the virus and the host’s genetic and epigenetic machinery is crucial for unraveling the mechanisms of viral pathogenesis and host response and shedding light on potential therapeutic avenues. This chapter explores the modulation of host genetic and epigenetic processes by SARS-CoV-2 infection, highlighting the intricate molecular interactions contributing to disease progression and variability in clinical outcomes. Drawing insights from recent research articles, this chapter delves into the impact of viral infection on gene expression, epigenetic modifications, and immune responses, shedding light on potential therapeutic targets for mitigating COVID-19 severity.