This report describes a detailed investigation of acetate-assisted C–H activation at PdIV centers supported by the tris­(2-pyridyl)­methane (Py3CH) ligand. Mechanistic information about this transformation has been obtained through the following: (i) extensive one- and two-dimensional NMR analysis, (ii) reactivity studies of a series of substituted analogues, and (iii) isotope effect studies. These experiments all suggest that C–H activation at (Py3CH)­PdIV(biphenyl)­Cl2+ occurs via a multistep process involving chloride-to-acetate ligand exchange followed by conformational and configurational isomerization and then C–H cleavage. The data also suggest that C–H cleavage proceeds via an acetate-assisted mechanism with the carboxylate likely serving as an intramolecular base. The viability of acetate-assisted C–H activation at high valent palladium has important implications for the design and optimization of catalytic processes involving this transformation as a key step.