The molecular docking studies were performed to determine the ligand interactions and their binding affinity with SARS-CoV-2 spike protein and main protease. The prepared ligands structures were docked against the binding sites of the target proteins. The HTVS docking approach filtered out a large number of compounds on the basis of their binding interactions within the binding sites of the target proteins. The compounds displaying a HTVS glide score of more than −6.0 kJ/mol were employed for XP docking. The docking simulations evaluated a high Glide score for the compounds with best binding affinity and their interactions within the binding pocket of the binding site residues. The docking analysis revealed a common compound, rutin (DrugBank ID: DB01698) which binds strongly to both the major targets of SARS-CoV-2. Our study here presents rutin exhibiting high binding efficiency against spike protein and main protease with an XP Glide score of −8.367 kcal/mol and −11.553 kcal/mol respectively. Rutin (3,3′,4′,5,7-pentahydroxyflavone-3-rhamnoglucoside) belongs to the flavonol class of compound, generously present in plants including buckwheat, apple, passion flower and tea. It is well known to exhibit many bioactivities, such as anti-viral, anti-bacterial, ant-larvicidal, cytoprotective, anticarcinogenic, antioxidant, vasoprotective, cardioprotective and neuroprotective activities (Saluja & Ganeshpurkar, 2016). The list of best ten candidates derived from the docking calculations with their corresponding docking score against spike protein and main protease are shown in supporting information (supporting material Tables S2 and S3). To determine the interaction pattern between rutin and target proteins, their docked complexes were visualized using Ligplot (Figure 1). The interaction pattern between rutin and spike protein revealed the formation of five hydrogen bonds and four hydrophobic interactions at the binding site, thereby contributing to the stability of the complex. The residues involved in the formation of hydrogen bonds between rutin and spike protein were F970, N969, H49, Q52, and T274. While the hydrophobic contact between the two involved residues T51, S50, S967 and S968. The interactions between rutin and main protease was stabilized by residues E166, T190, Y54, D187, T26, N142 forming hydrogen bond and various hydrophobic contacts with residues P168, L167, H41, G143, T25, L27, M49, M165, H164, R188 and Q189 (Tables 1 and 2). A similar study exploiting a blind molecular docking approach utilizing the Swiss Dock server also highlights main protease inhibition by rutin where by common amino acids viz. E166, T190, N142, H41 are found to be interacting with the inhibitor. In our study however, the inhibitor displayed slightly better binding efficiency than their report (Das et al., 2020). From the contact analyses of both proteins, it can be attributed that rutin has high affinity and wide molecular contacts for both spike protein and main protease. Also, it was further scrutinized by molecular dynamics simulations to attain insights towards the inhibitory aspects and efficacy to combat spike protein and main protease drug targets of SARS-CoV-2.