AbstractA predictive model, shaped as a set of rules, is presented that predicts site‐selectivity in the mono‐oxidation of diols by palladium‐neocuproine catalysis. For this, the factors that govern this site‐selectivity within diols and between different diols have been studied both experimentally and with computation. It is shown that an electronegative substituent antiperiplanar to the C−H bond retards hydride abstraction, resulting in a lower reactivity. This explains the selective oxidation of axial hydroxy groups in vicinal cis‐diols. Furthermore, DFT calculations and competition experiments show how the reaction rate of different diols is determined by their configuration and conformational freedom. The model has been validated by the oxidation of several complex natural products, including two steroids. From a synthesis perspective, the model predicts whether a natural product comprising multiple hydroxy groups is a suitable substrate for site‐selective palladium‐catalyzed oxidation.