Opuntia ficus-indica is a cactaceous plant native to America but, nowadays, widely found worldwide, having been the most common domesticated species of cactus grown as a crop plant in semiarid and arid parts of the globe, including several Mediterranean basin countries. Opuntia ficus-indica can be regarded as a medicinal plant, being source of numerous bioactive phytochemicals such as vitamins, polyphenols, and amino acids. The urgent need for therapeutic treatments for the COronaVIrus Disease 19 (COVID-19), caused by the Severe Acute Respiratory Syndrome (SARS)-Coronavirus (CoV)-2, justifies the great attention currently being paid not only to repurposed antiviral drugs, but also to natural products and herbal medications. In this context, the anti-COVID-19 utility of Opuntia ficus-indica as source of potential antiviral drugs was investigated in this work on the basis of the activity of some of its phytochemical constituents. The antiviral potential was evaluated in silico in docking experiments with Mpro, i.e., the main protease of SARS-CoV-2, that is one of the most investigated protein targets of therapeutic strategies for COVID-19. By using two web-based molecular docking programs (1-Click Mcule and COVID-19 Docking Server), we found, for several flavonols and flavonol glucosides isolated from Opuntia ficus-indica, good binding affinities for Mpro, and in particular, binding energies lower than −7.0 kcal/mol were predicted for astragalin, isorhamnetin, isorhamnetin 3-O-glucoside, 3-O-caffeoyl quinic acid, and quercetin 5,4′-dimethyl ether. Among these compounds, the chiral compound astragalin showed in our in silico studies the highest affinity for Mpro (−8.7 kcal/mol) and also a low toxicity profile, emerging, thus, as an interesting protease inhibitor candidate for anti-COVID-19 strategies.