Originating in the city of Wuhan in China in December 2019, COVID-19 has emerged now as a global health emergency with a high number of deaths worldwide . COVID-19 is caused by a novel coronavirus, referred to as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), resulting in pandemic conditions around the globe . We are in the battleground to fight against the virus by rapidly developing therapeutic strategies in tackling SARS-CoV-2 and saving human lives from COVID-19 . Scientists are evaluating several known drugs either for the pathogen or the host; however, many of them are reported to be associated with side effects . In the present study, we report the molecular binding mechanisms of the natural alkaloid, noscapine, for repurposing against the main protease of SARS-CoV-2, a key enzyme involved in its reproduction . We performed the molecular dynamics (MD) simulation in an explicit solvent to investigate the molecular mechanisms of noscapine for stable binding and conformational changes to the main protease (Mpro) of SARS-CoV-2 . The drug repurposing study revealed the high potential of noscapine and proximal binding to the Mpro enzyme in a comparative binding pattern analyzed with chloroquine, ribavirin, and favipiravir . Noscapine binds closely to binding pocket-3 of the Mpro enzyme and depicted stable binding with RMSD 0.1-1.9 Å and RMSF profile peak conformational fluctuations at 202-306 residues, and a Rg score ranging from 21.9 to 22.4 Å . The MM/PB (GB) SA calculation landscape revealed the most significant contribution in terms of binding energy with ΔPB -19.08 and ΔGB -27.17 kcal/mol . The electrostatic energy distribution in MM energy was obtained to be -71.16 kcal/mol and depicted high free energy decomposition (electrostatic energy) at 155-306 residues (binding pocket-3) of Mpro by a MM force field . Moreover, the dynamical residue cross-correlation map also stated that the high pairwise correlation occurred at binding residues 200-306 of the Mpro enzyme (binding pocket-3) with noscapine . Principal component analysis depicted the enhanced movement of protein atoms with a high number of static hydrogen bonds . The obtained binding results of noscapine were also well correlated with the pharmacokinetic parameters of antiviral drugs.