Calcium/calmodulin-dependent protein kinase IV (CaMKIV) is an upstream regulator of CaMKK-CaMKIV signaling cascade that activates various transcription factors, thereby regulating several cellular activities including, neuronal communication and immune response. Owing to the abnormal expression in cancer and neurodegenerative diseases, the CaMKIV has been considered a potential drug target. In the present study, we checked the binding affinity of plant-derived natural compounds viz., quercetin, ellagic acid (EA), simvastatin, capsaicin, ursolic acid, DL-α-tocopherol acetate, and limonin towards CaMKIV. Molecular docking and fluorescence binding studies showed that EA and quercetin bind to the CaMKIV with a considerable affinity in comparison to other compounds. Enzyme inhibition assay revealed that both EA and quercetin inhibit CaMKIV activity with their IC₅₀ values in the micromolar range. To get atomistic insights into the mode of interactions, inhibition mechanism, and the stability of the CaMKIV-ligand complex, a 100 ns MD simulation analysis was performed. Both EA and quercetin bind to the catalytically important residues of active site pocket of CaMKIV forming enough stabilizing interactions presumably inhibiting enzyme activity. Moreover, no significant structural change in the CaMKIV was observed upon binding of EA and quercetin. In conclusion, this study illustrates the application of phytoconstituents in the development of therapeutic molecules targeting CaMKIV having implications in cancer and neurodegenerative diseases after in vivo validation.