A series of esterified curcumin ligands containing structurally diverse acyl substituents were synthesized and used to prepare the corresponding neutral half-sandwich Ru(ii)–p-cymene complexes. All compounds were characterized by FT-IR, NMR spectroscopy, ESI mass spectrometry, and elemental analysis, while selected ligands and complexes were further confirmed by single-crystal X-ray diffraction. Density functional theory calculations provided additional insight into their structural and electronic properties. The antiproliferative activities of the ligands and ruthenium complexes were evaluated against human cancer cell lines (HepG2, Caco-2, MCF-7, A2780, and A2780cis) and non-tumorigenic controls (MCF10A and HEK293T). Overall, coordination to ruthenium enhanced the activity of the parent ligands, although the magnitude of this effect depended strongly on both the ester substituent and the cellular model. Among the compounds studied, the heptanoyl complex showed the highest activity in MCF-7 cells and was therefore selected for further investigation. DNA-binding studies, enzyme inhibition assays, and cellular biomarker analyses suggest that this compound combines increased DNA affinity with inhibition of the 20S proteasome and HMG-CoA reductase and promotes apoptotic signaling, as evidenced by DEVDase activity stimulation and Bcl-2 downregulation. Collectively, these results demonstrate that esterification of curcumin, together with Ru(ii)–arene coordination, is an effective strategy for tuning the anticancer profile of curcuminoid-based organoruthenium compounds.