A series of dehydrozingerone-based C-Mannich bases 6(a–e) were synthesized via condensation of dehydrozingerone, substituted aromatic aldehyde with various secondary amines. The structures were confirmed by FT-IR, NMR, and HR-MS spectral studies. The geometry, molecular orbitals, molecular electrostatic potential, and quantum descriptors of the derivatives were determined by density functional theory (DFT). Anticancer potential of the synthesized derivatives was studied by in vitro studies against a panel of cancerous cell lines and a normal healthy cell line. Compound 6a exhibited strong cytoxicity against A549 (lung), MCF-7 (breast), and Hep2 (colon) cancer cells, while compound 6c showed notable activitay against HeLa (cervical) and HepG2 (liver) cell lines. Notably, none of the compounds displayed cytoxicity toward normal cells, indicating good cytocompability and selectivity. Network pharmacology identified key targets, and molecular docking revealed strong binding affinities of the compounds with estrogen receptor alpha (ESR1), telomerase reverse transcriptase (TERT), and PIK3CA. Further in silico analysis predicted favourable physicochemical, pharmacokinetic, drug-likeness and low toxicity, including cardiotoxicity. These findings suggest that dehydrozingerone-based C-Mannich bases are promising candidates for further development as selective anticancer agents.