Molecular hybridization approach is a promising structural modification tool to design new chemical entities (NCEs) by mimicking two different pharmacophoric units into one scaffold to enhance the biological properties. With this aim, combretastatin‐A4 acids were integrated with sulfonyl piperazine scaffolds as a one molecular platform and evaluated for their in vitro antiproliferative activity against a panel of human cancer lines cell lines namely, lung (A549), mouse melanoma (B16F10), breast (MDA MB‐231and MCF‐7) and colon (HCT‐15) by MTT assay. Amongst which the compound (E)‐3‐(4‐Chlorophenyl)‐1‐(4‐((4‐chlorophenyl)sulfonyl)piperazin‐1‐yl)‐2‐(3,4,5‐trimethoxyphenyl)prop‐2‐en‐1‐one (5 ab) displayed significant IC₅₀ values in the range of 0.36 to 7.08 μm against the selected cancer cell lines. Moreover, 5 ab was found to be the most potent member of this series with IC₅₀ 0.36±0.02 μm. Further investigations revealed that the compound 5 ab displayed significant inhibition of tubulin assembly with IC₅₀ 5.24±0.06 μm and molecular docking studies also disclosed the binding of 5 ab effectively in CA4 binding space at the colchicine binding site. The flow cytometric analysis demonstrated that the compound 5 ab caused cell cycle arrest at G2/M phase in A549 cells. Compound 5 ab induced apoptosis in A549 cells which was further evaluated by different staining assays such as DAPI and AO which undoubtedly speculated, the induction of apoptosis. To study the anti‐migration with 5 ab, cell migration/scratch wound assay was performed and the extent of apoptosis was studied by Annexin‐V, including mitochondrial potential by JC‐1 staining.