A novel series of 1,2,3-triazole/quinazoline-4-one hybrids (8a–t) were designed and synthesized as dual-targeted antiproliferative agents. Compounds 8a–t were evaluated for their antiproliferative efficacy against a panel of four cancer cell lines. The results indicated that most of the evaluated compounds exhibited strong antiproliferative activity, with 8f, 8g, 8h, 8j, and 8l demonstrating the highest potency. These five compounds were investigated as EGFR and BRAFV600E inhibitors. The in vitro tests showed that compounds 8g, 8h, and 8j are strong antiproliferative agents that might work as dual EGFR/BRAFV600E inhibitors. Compounds 8g and 8h were further examined as activators of caspases 3, 8, and Bax and down-regulators of the anti-apoptotic protein Bcl2. The results indicated that the studied compounds had considerable apoptotic antiproliferative action. The investigation of the cell cycle and apoptosis …