Some new Bis-pyrazoline hybrids8–17with dual EGFR and BRAFV600Einhibitors have been developed. The target compounds were synthesized and tested in vitro against four cancer cell lines. Compounds12,15, and17demonstrated strong antiproliferative activity with GI50values of 1.05 µM, 1.50 µM, and 1.20 µM, respectively. Hybrids showed dual inhibition of EGFR and BRAFV600E. Compounds12,15, and17inhibited EGFR-like erlotinib and exhibited promising anticancer activity. Compound12is the most potent inhibitor of cancer cell proliferation and BRAFV600E. Compounds12and17induced apoptosis by increasing caspase 3, 8, and Bax levels, and resulted in the downregulation of the antiapoptotic Bcl2. The molecular docking studies verified that compounds12,15, and17have the potential to be dual EGFR/BRAFV600Einhibitors. Additionally, in silico ADMET prediction revealed that most synthesized bis-pyrazoline hybrids have low toxicity and adverse effects. DFT studies for the two most active compounds,12and15, were also carried out. The values of the HOMO and LUMO energies, as well as softness and hardness, were computationally investigated using the DFT method. These findings agreed well with those of the in vitro research and molecular docking study.