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COVID-19 pandemic waves hitting worldwide result in drastic postinfection complications with interindividual variations, which raised the question for the cause of these observed variations. This urged to think "the impact of environment-affected genes"? In an attempt to unravel the impact of environment-affected genes, a systematic rapid review was conducted to study "the impact of host or viral epigenetic modulation on COVID-19 infection susceptibility and/or outcome." Electronic databases including Web of Science, SCOPUS, Cochrane Central Register of Controlled Trials, PubMed, and Google Scholar, and other databases were searched. The search strings included "COVID-19" OR "SARS-CoV-2" AND (Epigenetics'). Articles with randomized clinical trials (RCTs) and observational study designs, conducted on humans and available in the English language, were selected, with respect to "The interplay between the SARS-CoV-2 virus and Epigenetics" published from 2020 to February 2021 (but not limited to 2020, being expanded to 2015). Database search yielded 1330 articles; after screening, exclusion, and further filtrations, 51 articles were included. Susceptibility to COVID-19 infection is related to the viral-microRNAs (miRNAs) which alter virulence of the transmitted SARS-CoV-2 strains and impact host-miRNA-related innate immunity. Host-DNA methylation and/or chromatin remodeling may be implicated in severe cytokine storm that can ultimately results in fatal outcome., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)