A DFT study of protonation thermodynamics in H2-evolving biomimetic catalysts related to [FeFe]-hydrogenases active site is presented here. Taking as a reference system the electrocatalytic dihydrogen evolution mechanism recently proposed for the synthetic assembly [Fe2(CO)4(κ2-Ph2PCH2CH2PPh2)(μ-S(CH2)3S)] (a, which is able to release H2 after having undergone monoelectron reduction steps and three sequential protonation reactions), we show how the reduction of model complexes to oxidation states lower than those observed in [FeFe]-hydrogenases cofactor leads to a protonation regiochemistry that has no counterpart in the enzymatic mechanism of H2 production. In particular, double protonation of the metal centers turned out to be disfavored in a by up to 12.5 kcal mol−1 with respect to alternative protonation paths; as for the regiochemistry of triple protonation, the formation of η2-H2 adducts is disfavored by at least ∼25 kcal mol−1. Structural analysis of the theoretical models also revealed that over-reduction of synthetic complexes, though necessary for observing H2 evolution from the currently available biomimetic electrocatalysts, can generally impair their structural integrity. Possible approaches for the modulation of protonation regiochemistry are then proposed; in particular, it turned out that a targeted use of σ-donating ligands showing low basicity can favor double protonation of iron centers.