Dual-specificity tyrosine phosphorylation-regulated kinases (DYRK1A, 1B, 2-4) and cdc2-like kinases (CLK1-4) are a part of CMGC group of kinases that play an important role in multiple cellular processes like signal transduction, cell cycle regulation, survival and neuronal development etc. Hence, aberrant expression and/or activity of some of these kinases are implicated in disorders like cancer, and neurodegenerative diseases. Consequently, targeting these kinases using small molecules has been an area of potential therapeutic interest in the aforementioned diseases. In the present research, we report the design, synthesis, and biological evaluation of some 4-arylidene-2-phenyloxazol-5(4H)-one derivatives as a novel class of inhibitors of Dual-specificity tyrosine phosphorylation-regulated kinases and cdc2-like kinases. Among the sixteen derivatives synthesized and evaluated, compound 12 with a 3-chloro and 4-hydroxyl substitution in the 4-arylidene ring demonstrated the best inhibitory profile against both Dual-specificity tyrosine phosphorylation-regulated kinases and cdc2-like kinases at micromolar to submicromolar concentrations. Molecular docking studies revealed that compound 12 can efficiently interact with the ATP-binding site of the aforementioned kinases.