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The SARS-CoV-2 main protease, also known as 3-chymotrypsin-like protease (3CL pro ), is a cysteine protease responsible for the cleavage of viral polyproteins pp1a and pp1ab, at least, at eleven conserved sites, which leads to the formation of mature nonstructural proteins essential for the replication of the virus. Due to its essential role, numerous studies have been conducted so far, which have confirmed 3CL pro as an attractive drug target to combat Covid-19 and have reported a vast number of inhibitors and their co-crystal structures. Despite all the ongoing efforts, D-peptides, which possess key advantages over L-peptides as therapeutic agents, have not been explored as potential drug candidates against 3CL pro . The current work fills this gap by reporting an in silico approach for the discovery of D-peptides capable of inhibiting 3CL pro that involves structure-based virtual screening (SBVS) of an in-house library of D-tripeptides and D-tetrapeptides into the protease active site and subsequent rescoring steps, including Molecular Mechanics Generalized-Born Surface Area (MM-GBSA) free energy calculations and molecular dynamics (MD) simulations. In vitro enzymatic assays conducted for the four top-scoring D-tetrapeptides at 20 μM showed that all of them caused 55-85% inhibition of 3CL pro activity, thus highlighting the suitability of the devised approach. Overall, our results present a promising computational strategy to identify D-peptides capable of inhibiting 3CL pro , with broader application in problems involving protein inhibition., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Hernández González, Eberle, Willbold and Coronado.)