Traditional medicines against COVID-19 have taken important outbreaks evidenced by multiple cases, controlled clinical research, and randomized clinical trials. Furthermore, the design and chemical synthesis of protease inhibitors, one of the latest therapeutic approaches for virus infection, is to search for enzyme inhibitors in herbal compounds to achieve a minimal amount of side-effect medications. Hence, the present study aimed to screen some naturally derived biomolecules with anti-microbial properties (anti-HIV, antimalarial, and anti-SARS) against COVID-19 by targeting coronavirus main protease via molecular docking and simulations. Docking was performed using SwissDock and Autodock4, while molecular dynamics simulations were performed by the GROMACS-2019 version. The results showed that Oleuropein, Ganoderic acid A, and conocurvone exhibit inhibitory actions against the new COVID-19 proteases. These molecules may disrupt the infection process since they were demonstrated to bind at the coronavirus major protease's active site, affording them potential leads for further research against COVID-19.