Background: Ligustrazine and chalcones have been reported previously for various biological activities including anticancer effects. Objectives: Based on the multitargeted biological activities approach of ligustrazine-based chalcones, in the current study 18 synthetic ligustrazine-containing α, β-unsaturated carbonyl-based 1, 3- Diphenyl-2-propen-1-one derivatives were evaluated for their inhibitory effects on the growth of five different types of cancer cells. Methods: All the compounds were evaluated for anticancer effects on various cancer cell lines by propidium iodide fluorescence assay and various other assays were performed for mechanistic studies. Results: A majority of compounds exhibited strong inhibition of cancer cells, especially synthetic compounds 4a and 4b, bearing 1-Pyridin-3-yl-ethanone as a ketone moiety in the main structural backbone were found to be most powerful inhibitors of cancer cell growth. Nine most active compounds among the whole series were selected for further studies related to different cancer targets, including EGFR TK kinases, tubulin polymerization, KAF and BRAF^V600E. Conclusion: Synthetic derivatives, including 4a-b and 5a-b showed a multitarget approach and strong inhibitory effects on EGFR, FAK and BRAF while three compounds, including 3e bearing methoxy substitution, 4a and 4b with 1-pyridin-3-yl-ethanone moiety showed the inhibition of tubulin polymerization.