The formation of M-Zn-intermetallic species (M = Ni, Pd) in the course of the Negishi reaction in THF solvent and their potential impact on in situ catalyst inhibition were investigated by DFT calculations carried out at two levels of theory. The solvent coordination to the transition metal centers was explicitly accounted for in the calculations. Two model PR₃ ligands (PR₃ = PMe₃ and PPh₃), as well as a model NHC-type ligand (1,3-diisopropylimidazol-2-ylidene), were selected. The formation of the intermetallic species during the catalytic process effectively removes the key in-cycle cross-coupling intermediates M(0)L₂, cis-[L₂PhM(ii)X], and trans-[L₂PhM(ii)X] from the main Negishi catalytic cycle. The reaction between the ZnX₂ by-product of the cross-coupling and the M(0)L₂ species yields bi-metallic adducts with M-Zn dative bonds. The nature of these bonds in the resulting complexes was analyzed with QTAIM. ZnX₂ coordination to [L₂PhM(ii)X] intermediates prevents the binding of alkylzinc halide (RZnX) reagents and blocks the cross-coupling process. Based on these findings, we consider LiX additives as agents that passivate the Lewis-acidic ZnX₂ by-product and therefore limit the product inhibition. This work highlights the profound effect of a system view on catalytic cross-coupling reactions, where interactions between components of catalytic systems are taken into account explicitly, and discourage the use of single-cycle-only models.