The main protease (M) of SARS-CoV-2 plays a crucial role in viral replication and is a prime target for therapeutic interventions. Phytochemicals, known for their antiviral properties, have been previously identified as potential M inhibitors in several in silico studies. However, the efficacy of these remains in question owing to the inherent flexibility of the M binding site, posing challenges in selecting suitable protein structures for virtual screening. In this study, we conducted an extensive analysis of the M binding pocket, utilizing molecular dynamics (MD) simulations, principal component analysis (PCA) and free energy landscape (FEL) to explore its conformational diversity. Based on pocket volume and shape-based clustering, five representative protein conformations were selected for virtual screening. Virtual screening of a library of ~ 48,000 phytochemicals suggested 39 phytochemicals as potential M inhibitors. Based on subsequent MM-GBSA binding energy calculations and ADMET property predictions, five compounds were advanced to cell-based viral replication inhibition assays, with three compounds (demethoxycurcumin, shikonin, and withaferin A) exhibiting significant (EC50 < 10 μm) inhibition of SARS-CoV-2 replication. Our study provides an understanding of the binding interactions between these phytochemicals and M, contributing significantly to the identification of promising M inhibitors. Furthermore, beyond its impact on therapeutic development against SARS-CoV-2, this research highlights a crucial role of proper nutrition in the fight against viral infections.