A novel set of quinazoline-4-one/1,2,4-oxadiazole hybrids (9a-o) was designed and synthesized as EGFR, EGFR^T790M, and BRAF^V600E inhibitors in the search for multitargeted antiproliferative scaffold. The novel hybrids showed encouraging antiproliferative actions. Compounds 9b, 9c, 9h, 9k, and 9l were evaluated as EGFR and BRAF^V600E inhibitors. These in vitro experiments demonstrated that compounds 9b, 9c, and 9h are potent antiproliferative agents capable of acting as dual EGFR/BRAF^V600E inhibitors. 9b, 9c, and 9h were further studied for their inhibitory effect on mutant EGFR (EGFR^T790M), with the results indicating that the evaluated compounds had a significant inhibitory effect. Cell cycle analysis and apoptosis induction assay of 9b revealed cell cycle arrest at the G2/M phase, which can induce apoptosis. EGFR and BRAF^V600E docking simulations inside their active regions shed light on these compounds’ possible modes of inhibition. ADME calculations revealed that all test compounds satisfy Lipinski’s rule of five (RO5) with MLogP <5, with easy transport through cell membranes and higher oral bioavailability. These new hybrids may have potential as anti-cancer drugs after optimization.