The enantioselective hydrogenation of 4-hydroxy-6-methyl-2-pyrone (1a), 3,6-dimethyl-4-hydroxy-2-pyrone (2a), 4-methoxy-6-methyl-2-pyrone (3a), and 4,6-dimethyl-2-pyrone (4a) was studied over a 5 wt% Pd/TiO2 catalyst. Various cinchona alkaloids and their O- and N-methyl derivatives were applied as chiral modifiers. The catalytic experiments combined with FTIR, NMR, and NOESY-NMR spectroscopic analysis and ab initio calculations revealed an interesting feature of the reactions: the ee is determined by competing reactant–modifier interactions. These interactions may involve the OH function and the quinuclidine N of the alkaloid modifier. When the reactant possesses an acidic OH group (1a and 2a), the reaction via the energetically most stable bidentate complex controls the enantioselectivity. Protic or basic solvents diminish the ee in these reactions by stabilizing a single-bonded (acid–base type) interaction. Different mechanisms are proposed for the hydrogenation of the nonacidic pyrones 3a and 4a. These models can well interpret the catalytic results but require further confirmation. Besides, the studies provided the first experimental evidence for an intrinsic rate acceleration coupled with the enantiodifferentiating process over chirally modified Pd.