Nickel(II) complexes of mono-functionalized pyridine-tetraazamacrocycles (PyMACs) are a new class of catalysts that possess promising activity similar to biological peroxidases. Experimental studies with ABTS (2,20-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid), substrate) and H2O2 (oxidant) proposed that hydrogen-bonding and proton-transfer reactions facilitated by their pendant arm were responsible for their catalytic activity. In this work, density functional theory calculations were performed to unravel the influence of pendant arm functionalization on the catalytic performance of Ni(II)-PyMACs. Generated frontier orbitals suggested that Ni(II)-PyMACs activate H2O2 by satisfying two requirements: (1) the deprotonation of H2O2 to form the highly nucleophilic HOO-, and (2) the generation of low-spin, singlet state Ni(II)-PyMACs to allow the binding of HOO-. COSMO solvation-based energies revealed that the O-O Ni(II)-hydroperoxo bond, regardless of pendant arm type, ruptures favorably via heterolysis to produce high-spin (S = 1) [(L)Ni3+-O]2+ and HO-. Aqueous solvation was found crucial in the stabilization of charged species, thereby favoring the heterolytic process over homolytic. The redox reaction of [(L)Ni3+-O]2+ with ABTS obeyed a 1:2 stoichiometric ratio, followed by proton transfer to produce the final intermediate. The regeneration of Ni(II)-PyMACs at the final step involved the liberation of HO-, which was highly favorable when protons were readily available or when the pKa of the pendant arm was low.