Titanocene derivatives exhibit high potential in the treatment of cisplatin-resistant tumor types. Density functional theory calculations were performed on the hydrated form of five drug candidates differing in the pendant arms attached to the aromatic rings. A qualitative correlation has been found between the experimentally measured anticancer activity of alkylammonium-functionalized titanocene derivatives and the computed free energy change of the proton-induced dissociation reaction of these compounds. The results indicate that differences in the cytotoxic activities could be related to the solvation properties of the protolysis products, whereas no correlation was found with gas-phase properties of these molecules. Contrary to the free energy change of the protolysis reaction, other molecular properties, such as the geometrical parameters or the binding energies of the cyclopentadienyl rings in solution, do not correlate with the in vitro cytotoxic activity of these drug candidates.