Nelfinavir and lopinavir are viral protease inhibitors used against HIV infection but are reported to possess high cytotoxic effects. Lopinavir and ritonavir are viral protease inhibitors recommended for the treatment of SARS and MERS having similar mechanisms of action as nelfinavir and lopinavir. (Miyamoto and Kollman, 1992). To elucidate the binding affinity, docking studies of various withanolides found in WS were carried out on human ACE2 receptor, SARS-CoV and SARS-CoV-2 specific proteins. Among various phytoconstituents, withanolide A displayed strong binding affinity to SARS-CoV spike glycoprotein (BE: −9.78 kcal/mol, Kd: 67.23 nM), SARS-CoV-2 spike glycoprotein (BE: −7.18 kcal/mol, Kd: 5.48 µM), SARS-CoV 3CL-pro main protease (BE:-8.93 kcal/mol, Kd: 285.01 nM) and SARS-CoV-2 Nsp10/Nsp-16 complex (BE: −10.38 kcal/mol, Kd: 24.67 nM). On the basis of binding energy, withanolides A and B and withanone were found to be the most effective phytocomponents in WS. The present study reports for the first time the antiviral efficacy of medicinal herbs like Withania somnifera that form the crux of Ayurveda, the Indian traditional system of medicine as a viable alternative to chemosynthetic drugs for preventing/blocking entry of SARS-CoV-2 into host cells and also inhibiting viral main protease.