Background: COVID-19 remains a major global challenge while several drugs identified to ameliorate the syndromes are associated with incessant resistance and lack of prospective potentials to permanently curb the infection. This study is aimed at evaluating the potentials of the existing drug molecules to overcome the viral resistance through multi-target inhibition mechanisms. Methods: Molecular docking and molecular dynamics simulations have been extensively applied to virtually screen 2826 drugs from Selleckem.com library against some key bio-receptors implicated in the SARS-CoV-2 such as the viral nucleocapsid phosphoprotein, the viral spike glycoprotein and the human host ACE2. Results: Five drugs namely D-(+)-Raffinose pentahydrate (1), (-)-Epicatechin gallate (5), 2797 (7), Rutin DAB10 (8) and Hyperoside (9) display higher inhibitory potentials against N-terminal NTD of SARS-CoV-2 (PDB 6M3M) with XP docking scores of -16.20, -11.98, -11.83, -11.81 and -11.41 than remdesivir and ribavirin with -10.27 and -9.06 respectively. Their estimated binding free energies against the receptor are -27.80, -27.91, -32.39, -27.91 and -29.50 kcal/mol compared to remdesivir and ribavirin with -24.27 and -15.37 kcal/mol respectively. Similar inhibition patterns were observed against the viral S-protein and the human ACE2 with high stability and bio-functionality. Conclusion: The identified compounds show promising potentials amenable for breakthrough against the drug-resistant COVID-19 upon further studies.