Using a bioinformatic analysis of human miRNA potential interactions with the SARS-CoV-2’s genome, we examined the potential miRNA target sites in 7 coronavirus genomes that include SARS-CoV-2, MERS-CoV, SARS-CoV, and 4 non-pathogenic coronaviruses. (Data Set 1). Our approach was to examine and compare 3 pathogenic and 4 non-pathogenic strains of HCoVs. The HCoVs' RNA genomes of pathogenic strains were SARS-CoV-2 (NC_045512.2), SARS-CoV (NC_004718.3), MERS-CoV (NC_019843.3). The non-pathogenic strains were HCoV-OC43 (KU131570.1), HCoV-229E (NC_002645.1), HCoV-HKU1 (KF686346.1), and HCoV-NL63 (NC_005831.2). These coronaviruses were tested against the set of 896 confident mature human miRNA sequences that were obtained from the miRBbase v2.21 using the RNA22 v2 microRNA target discovery tool web-server. In order to reduce the false discovery rate of the MTS predictions, the most strict parameters were applied to the default computation workflow using a specificity of 92% versus a sensitivity of 22%. In Data set 2, using the miRDIP database with only top 1% of the most probable targets considered, we analyzed the potential targets of miRNA that could be bound to either the pathogenic, the non-pathogenic or both groups of HCoVs. In Data set 3, using miRNAFold webserver we identified 10 pre-miRNA sequences in the SARS-CoV-2 RNA sequence that could potentially enter the human RNAi pathway. The graphical summary of our working hypothesis is provided in the graphical abstract.