The COVID-19 pandemic has claimed more than a million lives worldwide within a short time span. Due to the unavailability of specific antiviral drugs, critically sick patients of COVID-19 are at the risk of developing multiorgan failure syndrome and higher mortality rate. Despite the discovery of vaccines against the causative agent SARS-CoV-2, the chances of breakthrough infections are on rise due to the emergence of several new viral strains. Therefore, an urgent discovery and development of effective antiviral drug for the treatment of COVID-19 is highly desired. Targeting the main protease (Mpro) of SARS-CoV-2 has great potential for drug discovery and drug repurposing efforts. Published crystal structures of SARS-CoV-2 Mpro has expediated the lead/drug discovery campaign, particularly via the in silico screening of multiple libraries of synthetic compounds to cover diverse chemical space. The present study aimed to screen 4 libraries of synthetic flavonoids and one library of benzisothiazolinones as potential SARS-CoV-2 Mpro inhibitors using computational methods. The short-listed compounds after virtual screening were filtered through SwissADME modelling tool to remove molecules with unfavorable pharmacokinetics and medicinal properties. The drug-like molecules were further subjected to iterative docking for the identification of top binders of SARS-CoV-2 Mpro. Finally, the molecular dynamic (MD) simulations and MM-GBSA binding free energy calculations were performed for the evaluation of the dynamic behavior, stability of protein–ligand complex, and binding affinity, resulting in the identification of thioflavonol, TF-9 as a potential inhibitor of the Mpro. The computational studies further revealed the binding of TF-9 close to the catalytic dyad and interactions with conserved residues in the S1 subsite of the active site. Our in-silico study demonstrated that synthetic analogs of flavonoids, particularly thioflavonols, have a strong tendency to inhibit the main protease Mpro, and thereby inhibit the reproduction of SARS-CoV-2.