This study carried out a full-scale in silico investigations on natural quinazoline alkaloids against the main protease (M Pro ) of SARS_CoV_2. This study examined 41 natural quinazoline alkaloids which are far greater in sample number compared to earlier reports and identified three alkaloids (CNP0416047, 3-hydroxy anisotine and anisotine as hit compounds. Furthermore, the structure-based binding of these hits was investigated through advanced flexible docking and Epharmacophore mapping. Moreover, hit alkaloids were also subjected to DFT based calculation to measure the electron distribution on the frontier molecular orbitals in support of their reactivity at the binding site of M Pro . Finally, the stabilities of complexes of hit alkaloids with the protein target were accessed extensively using robust molecular dynamics simulation through RMSD, RMSF, Rg, and MM-PBSA values. Thus, this study identifies three natural quinazoline alkaloids as potential inhibitors of M Pro through extensive computational analysis. Overall, this study provides three natural quinazoline alkaloids as potential inhibitors of the main protease (M Pro ) of SARS_CoV_2 through detailed computational methods, adds values to quinazoline pharmacophore which is a fascinating natural product and opens the possibilities of in vitro studies of these hit alkaloids in future.