•19 compounds from Neem extract tested against 7 standard anti-COVID drugs for action on PLpro of latter.•All 19 NEEM molecules show better docking, ADME results vis-a-vis standard drugs.•Among the 19, desacetylgedunin (DCG) gives highest docking score with PLpro.•MD simulation of shows binding with DCG induces large structural change on PLpro. Azadirachta Indica (Neem) extracts have been known for their anti-bacterial and other effects since ancient times. The present work examines the inhibitory activity of Neem extracts on Papain like protease (PLpro) of the novel coronavirus SARS-CoV-2. The activity is analysed by molecular docking study along with molecular dynamics simulation. All the studied Neem compounds showed decent level of inhibitory activity against PLpro of SARS-CoV-2. Among them, desacetylgedunin (DCG) found in Neem seed showed the highest binding affinity towards PLpro. Furthermore, MD-simulation studies supported by standard analysis (e.g. root mean square deviation and fluctuation (RMSD, RMSF), radius of gyration, solvent accessible surface area (SASA)) showed large impact on the structure of PLpro by DCG. We believe that the significant effect of DCG on PLpro may help in therapeutic efforts against SARS-CoV-2. Display omitted