<p>SARS‑CoV‑2 has been well-known to cause the COVID-19 outbreak. Among the viral proteins, Main protease (M^pro) functions as an essential element of the SARS-CoV-2 life cycle, making it a key target for developing potential drug candidate to prevent COVID-19. To identify plant-based compounds using the IMPPAT database that could inhibit M^pro of SARS-CoV-2, a structure-guided integrated virtual screening was employed. The initial hits for potential drug candidates targeting M^pro were screened by assessing their pharmacological and physicochemical properties, ensuring their potential as drug candidates, followed by a Pan-assay interference compounds (PAINS) filter to eliminate molecules that may cause false positive results due to non-specific binding. Subsequently, the compounds demonstrating specific interactions and significant binding affinities towards the active site residue (e.g., Cys145) in the M^pro were further analyzed using essential dynamics and molecular dynamics simulations. Findings were further supported by MM-PBSA results. Finally, two phytochemicals, Amorphispironon E and Papaverrubine E, were identified which act on the active site of SARS-CoV-2 M^pro displaying potential antiviral efficacy.</p> Graphical Abstract <p>Schematic representation of SARS-CoV-2 life cycle, highlighting the role of M^pro and the mechanism of action of phytochemicals, amorphispironon E and Papaverrubine E</p>