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The COVID-19 pandemic outbreak prompts an urgent need for efficient therapeutics, and repurposing of known drugs has been extensively used in an attempt to get to anti-SARS-CoV-2 agents in the shortest possible time. The glycoside rutin shows manifold pharmacological activities and, despite its use being limited by its poor solubility in water, it is the active principle of many pharmaceutical preparations. We herein report our in silico and experimental investigations of rutin as a SARS-CoV-2 Mpro inhibitor and of its water solubility improvement obtained by mixing it with l-arginine. Tests of the rutin/l-arginine mixture in a cellular model of SARS-CoV-2 infection highlighted that the mixture still suffers from unfavorable pharmacokinetic properties, but nonetheless, the results of this study suggest that rutin might be a good starting point for hit optimization., This research was in part founded with POR FESR 2014/2020, and thus, Regione Umbria is gratefully acknowledged (S.M.). This work was supported by Fundación hna (to A.V.-C. and O.A.); Fondo Investiga Covid-19 del Instituto de Investigación Sanitaria de Aragón IIS-A (to O.A. and A.V.-C.); Miguel Servet Program from Instituto de Salud Carlos III (CPII13/00017 to O.A.); Fondo de Investigaciones Sanitarias from Instituto de Salud Carlos III and the European Union (ERDF/ESF, ”Investing in your future”) (PI18/00349 to O.A. and a FIS Research Contract to L.C.-L.); Spanish Ministry of Economy and Competitiveness (BFU2016-78232-P to A.V.-C.); Spanish Ministry of Science, Innovation and Universities (FPI Predoctoral Research Contract BES-2017-080739 to D.O.-A.); Diputación General de Aragón (Predoctoral Research Contract 2019 to A.J.-A., ‘Protein Targets and Bioactive Compounds Group’ E45_20R to A.V.-C., ‘Digestive Pathology Group’ B25_20R to O.A.); and Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas (CIBERehd).This work was supported by the subsidy from the Polish Ministry of Science and Higher Education for research on SARS-CoV-2, a grant from the National Science Center UMO-2017/27/B/NZ6/02488, and EU-Horizon2020 ITN OrganoVir grant 812673 to KP.