Density functional theory computations have elucidated the detailed mechanism and intriguing selectivities of C­(sp3)–H activation and arylation of aldehydes and ketones promoted by palladium–amino acid cooperative catalysis. The amino acid cocatalyst takes up the carbonyl substrate by a condensation reaction to form an imine–acid, which acts as a transient directing reagent and metathesizes with Pd­(OAc)2 (the precatalyst) to initiate active Pd­(II) complexes. The reaction then proceeds through C–H bond activation, oxidative addition of Pd­(II) by iodobenzene, and reductive elimination from Pd­(IV) completing C–C bond formation, followed by ligand exchange to regenerate the active Pd­(II) catalyst and release the arylated imine–acid which continues on hydrolysis to give the final product and regenerate the amino acid cocatalyst. The C–H activation step via concerted metalation–deprotonation (CMD), which is rate- and selectivity-determining, favors palladacyclic transition states with a minimum chelate ring strain and an optimal Pd­(d)/C–H­(σ) orbital interaction. This finding reveals the origins of the regioselectivities that favor (1) the benzylic C­(sp3)–H over ortho-phenyl C­(sp2)–H activation for aromatic aldehydes and (2) the β-primary C­(sp3)–H over γ-primary C­(sp3)–H activation for aliphatic ketones. Incorporation of a chiral amino acid into the catalyst allows for enantioselective benzylic C­(sp3)–H arylation of aromatic aldehydes, and the enantioselectivity arises from steric and torsional strains that discriminate between the diastereomeric transition states. The computational results demonstrate rich experimental–theoretical synergy and provide useful insights for the further development of C–H functionalization and metal–organic cooperative catalysis.