Background: Drug resistance is a critical problem in health care that affects therapy outcomes and requires new approaches to drug design. SARS-CoV-2 M{}^{\text{pro}} mutations are of concern as they can potentially reduce therapeutic efficacy. Viral infections are amongst the many disorders for which nutraceuticals have been employed as an adjunct therapy. The aim of this study was to examine the potential in vitro activity of L-arginine and vitamin C against SARS-CoV-2 M{}^{\text{pro}}. Methods: The M{}^{\text{pro}} inhibition assay was developed by cloning, expression, purification, and characterization of M{}^{\text{pro}}. Selected compounds were then screened for protease inhibition. Results: L-arginine was found to be active against SARS-CoV-2 M{}^{\text{pro}}, while a vitamin C/L-arginine combination had a synergistic antiviral action against M{}^{\text{pro}}. These findings confirm the results of our previous in silico repurposing study that showed L-arginine and vitamin C were potential M{}^{\text{pro}} inhibitors. Moreover, they suggest a possible molecular mechanism to explain the beneficial effect of arginine in COVID patients. Conclusions: The findings of the current study are important because they help to identify COVID-19 treatments that are efficient, inexpensive, and have a favorable safety profile. The results of this study also suggest a possible adjuvant nutritional strategy for COVID-19 that could be used in conjunction with pharmacological agents.