Covid 19 caused by novel strain SARS- CoV-2 has become a pandemic due to its contagious nature of infection. It enters by binding with ACE2 receptor present on the outer surface of a cell by cleaving S1/S2 with proteolytic protein Furin. Further viral replication or transcription then takes place with the help of main protease 3CLpro and polymerase RdRp. This in silco study was carried out to block ACE2, Furin, 3CLpro and RdRP with various phytochemicals to prevent SARS- CoV-2 entry and replication or transcription. Twenty different phytochemicals were screened to understand the drug-likeliness obeying Lipinski’s rule 5 and further, molecular docking was performed using these phytochemicals to block their respective target proteins. All the phytochemicals follow Lipinski’s rule of five and molecular docking result shows best binding affinity of Podofilox − 7.54 kcal/mol with ACE2, Psoralidin − 8.04 kcal/mol with Furin, Ursolic acid − 8.88 kcal/mol with 3CLpro and Epiafzelechin − 8.26 kcal/mol with RdRp. Thus, blocking two human receptors ACE2 and Furin with Podofilox and Psoralidin respectively may prevent the viral entry into the cells. Also blocking viral proteins 3CLpro and RdRp with Ursolic acid and Epiafzelechin may prevent viral replication or transcription. Using this combination therapy of blocking the receptors responsible for viral entry and viral proteins responsible for replication or transcription may prevent SARS- CoV-2 infection. © 2021, Indian Virological Society.