Recent studies have shown that combining kinase inhibitors has additive and synergistic effects. BRAF V600E and p38 αhave been extensively studied as potential therapeutic targets for a variety of dis- eases. In keeping with our interest in developing multi-targeted anticancer agents, a series of novel triaryl-imidazole-based analogues containing 3-aryl-1,2,4-oxadiazoles moiety ( 4a-h , Scaffold B) and their reaction intermediates aryl carboximidamides moiety ( 3a-h, Scaffold A) have been rationally designed, synthesized, and evaluated in vitro for their antiproliferative activity as dual p38 α/BRAF V600E inhibitors. The results revealed that the presence of the carboximidamide moiety is required for activity, and the best activity correlates with the Ar = 1,2-benzodioxole ( 3e ) ≥4-CH 3 O-C 6 H 5 -( 3c ) > 2-naphthyl (3h) > 4-Cl-C 6 H 5 ( 3b ). Ring closure of carboximidamide to 1,2,4-oxadiazole significantly reduces the activity. The results of docking study into p38 αrevealed higher binding affinities for compounds 3c, 3e , and 3h compared to the co-crystallized ligand, SB2. However, the docking study of compounds 3c and 3e into BRAF V600E revealed slightly lower affinities than vemurafenib.