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• In silico techniques were utilized to identify potential inhibitory agents. • Selected potential inhibitors belong to the class coumarin (1) and benzophenone (2). • Compounds 1 and 2 binds strongly to the 3-CLpro with -6.3 and -6.8 kcal/mol affinity. • Compounds 1 and 2 inhibited pro inflammatory cytokines. • Compounds 1 and 2 inhibited reactive oxygen and nitrogen species. Cytokine release syndrome (CRS) is an immunological complication, presented with a hyperactivated immune response, and has fatal consequences. Along with iatrogenic and monogenic causes, recently viral-induced CRS emerged as a global pandemic. There is an urgent need for new therapeutic compounds having immunomodulatory and viral protease inhibitory effects. Herein we report the coumarin (1) and benzophenone (2) derivatives as an inhibitor of pro-inflammatory mediators, IFN-γ, TNF-α, IL-1β, IL-6, GM-CSF, IL-2, reactive oxygen species (ROS), and nitric oxide (NO) in an in vitro study. The docking results indicate that both compounds 1 and 2 bind strongly to the target protein 3-chymotrypsin like protease (3-CLpro) with -6.3 and -6.8 kcal/mol binding affinity. Identification of binding site interactions revealed that both compounds formed stable interactions with the active site of 3-Chymotrypsin like protease (3-CLpro) by offering strong hydrophilic and hydrophobic interactions that helped in the inhibition of the target protein which highlights their anti-viral potential. Compounds 1 and 2 are the possible drug candidate for viral infections and associated cytokine release syndrome. [Display omitted] [ABSTRACT FROM AUTHOR]