The replacement of an acetate ligand for carbonate leads to a reversal in site-selectivity in the Pd-mediated C–H oxidative coupling of benzo[h]quinoline with 1,3-dimethoxybenzene. This report describes Density Functional Theory studies designed to elucidate the origin of this selectivity change. These studies focused on two key mechanistic steps: C–H activation and C–C bond-forming reductive elimination. We considered monometallic and bimetallic reaction pathways for acetate and carbonate conditions. The favored C–H activation pathway proceeds via a concerted metalation deprotonation (CMD) mechanism, independent of the nature of anionic ligand (acetate versus carbonate). The predicted selectivity is ortho/para for the C–H activation for both the acetate and carbonate-ligated Pd complexes. Further, we determined that the reductive elimination step is greatly facilitated by the coordination of benzoquinone (by ΔΔG‡ ∼ 20 kcal mol−1) and is predicted to be meta–meta selective with both anionic ligands. Overall, the DFT studies indicate that the anionic ligand does not induce a mechanism change at the elementary steps, and the predicted selectivity at all steps is equivalent for carbonate and acetate, no matter whether a dinuclear or mononuclear pathway is considered. These studies lead us to propose that the role of the anionic ligand is to control which step of the mechanism is overall selectivity-determining. This proposal has been tested experimentally using appropriately designed experiments. Notably, the insoluble base MgO as an acid trap under acetate conditions (with the aim of making the C–H insertion step less reversible), gave rise to predominant ortho/para selectivity in the presence of acetate, in analogy to the results previously seen under carbonate conditions.