Severe acute respiratory syndrome-related coronavirus-2 (SARS-CoV-2) pathogenesis is initiated by the binding of SARS-CoV-2 spike (S) protein with the angiotensin-converting enzyme 2 receptor (ACE2R) on the host cell surface. The receptor-binding domain (RBD) of the S protein mediates the binding and is more prone to mutations resulting in the generation of different variants. Recently, molecules with the potential to inhibit the interaction of S protein with ACE2R have been of interest due to their therapeutic value. In this context, the present work was performed to identify potential RBD binders from the Indian medicinal plant's phytochemical database through virtual screening, molecular docking, and molecular dynamic simulation. Briefly, 1578 compounds filtered from 9596 phytochemicals were chosen for screening against the RBD of the native SARS-CoV-2 S protein. Based on the binding energy, the top 30 compounds were selected and re-docked individually against the native and five variants of concern (VOCs: alpha, beta, gamma, delta, and omicron) of SARS-CoV-2. Four phytochemicals, namely withanolide F, serotobenine, orobanchol, and gibberellin A51, were found to be potential RBD binders in native and all SARS-CoV-2 VOCs. Among the four, withanolide F exhibited lower binding energy (− 10.84 to − 8.56 kcal/mol) and better ligand efficiency (− 0.3 to − 0.25) against all forms of RBD and hence was subjected to a 100 ns MD simulation which confirmed its stringent binding to the RBDs in native and VOCs. The study prioritizes withanolide F as a prospective COVID-19 (Coronavirus disease) therapeutic agent based on the observations. It warrants deeper investigations into the four promising leads for understanding their precise therapeutic value. Graphical abstract: [Figure not available: see fulltext.].