Replacement of [Pd(H2O)4]2+ by cis-[Pd(en)(H2O)2]2+, [PdCl4]2−, and [Pd(NH3)4]2+ on the hydrolytic cleavage of the Ace-Ala-Lys-Tyr-Gly–Gly-Met-Ala-Ala-Arg-Ala peptide is theoretically investigated by using different quantum chemical methods both in the gas phase an in water solution. First, we carry out a series of validation calculations on small Pd(II) complexes by computing high-level ab initio [MP2 and CCSD(T)] and Density Functional Theory (B3LYP) electronic energies while solvent effects are taken into account by means of a Poisson-Boltzmann continuum model coupled with the B3LYP method. After having assessed the actual performance of the DFT calculations in predicting the stability constants for selected Pd(II)-complexes, we compute the relative free energies in solution of several Pd(II)–peptide model complexes. By assuming that the reaction of the peptide with cis-[Pd(en)(H2O)2]2+, [Pd(Cl)4]2−, and [Pd(NH3)4]2+ would lead to the initial formation of the respective peptide-bound complexes, which in turn would evolve to afford a hydrolytically active complex [Pd(peptide)(H2O)2]2+ through the displacement of the en, Cl−, and NH3 ligands by water, our calculations of the relative stability of these complexes allow us to rationalize why [Pd(H2O)4]2+ and [Pd(NH3)4]2+ are more reactive than cis-[Pd(en)(H2O)2]2+ and [PdCl4]2− as experimentally found.