COVID-19 disease has had a global impact on human health with increased levels of morbidity and mortality. There is an unmet need to design and produce effective antivirals to treat COVID-19. This study aimed to explore the potential ability of natural stilbenes to inhibit the Mpro protease, an acute respiratory syndrome coronavirus-2 (SARS-CoV-2) enzyme involved in viral replication. The binding affinities of stilbene compounds against Mpro were scrutinized using molecular docking, prime molecular mechanics-generalized Born surface area (MM-GBSA) energy calculations, and molecular dynamic simulations. Seven stilbene molecules were docked with Mpro and compared with GC376 and N3, antivirals with demonstrated efficacy against Mpro. Ligand binding efficiencies and polar and non-polar interactions between stilbene compounds and Mpro were analyzed. The binding affinities of astringin, isorhapontin, and piceatannol were −9.319, −8.166, and −6.291 kcal/mol, respectively, and higher than either GC376 or N3 at −6.976 and −6.345 kcal/mol, respectively. Prime MM-GBSA revealed that these stilbene compounds exhibited useful ligand efficacy and binding affinity to Mpro. Molecular dynamic simulation studies of astringin, isorhapontin, and piceatannol showed their stability at 300 K throughout the simulation time. Collectively, these results suggest that stilbenes such as astringin, isorhapontin, and piceatannol could provide useful natural inhibitors of Mpro and thereby act as novel treatments to limit SARS-CoV-2 replication.