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AbstractBackground: COVID-19 is still instigating significant social and economic chaos worldwide; however, there is no approved antiviral drug yet. Here, we applied computational methods to analyze the structural basis of potential SARS-CoV-2 main protease (Mpro) inhibitors extracted from the essential oil of Thymus schimperi which could provide structural insights to discover potent anti-SARS-CoV-2 phytochemicals.Methods: Data on SARS-CoV-2 Mpro amino acid sequence were retrieved from national center for biotechnology information (NCBI). T-Coffee was used to determine multiple sequence while phylogenetic tree was constructed using DNA star (DNASTAR, Inc.). The absorption, distribution, metabolism, excretion, and toxicity (ADMET) profiles of compounds was determined through SwissADME and ProToxII servers. AutoDock tools were used for molecular docking analysis while Chimera, DS studio and LigPlot were used for post docking studies. Molecular dynamic simulations were performed for 200 ns under constant pressure. Figures were illustrated using PyMoL.Results: Evolutionary relationship analysis showed that SARS-CoV-2, SARS-CoV and Bat-CoV Mpro are distantly related with human, rat and MERS-CoV Mpro. High substitution frequency was observed between threonine and serine, alanine and serine, arginine and serine, and arginine and asparagine. All compounds have a bioavailability score of ≥ 0.55 entailing that at least 55% of drugs can be absorbed unchanged. Only five (9%), nine (16%) and two (3.6%) of the compounds exhibited active hepatotoxicity, carcinogenicity and immunotoxicity, respectively. Except for flourazophore P with a little mutagenicity, all other compounds didn’t show mutagenic properties. On the other hand, only pinene beta was found to have a little cytotoxicity. Five compounds demonstrated effective binding to the catalytic dyad of the SARS-CoV-2 Mpro substrate binding pocket while two of them (geranylisobutanoate and 3-Octane) are found to be the best hits that formed hydrogen bonds with Glu166 and Ser144 of SARS-CoV-2 Mpro.Conclusion: Based on our in-silico analysis, top hits from Thymus schimperi may serve as potential anti-SARS-CoV-2 compounds. Further in vitro and in vivo studies are recommended to characterize these compounds for clinical applications.