Oxidation presents a constant challenge for formulation scientists trying to develop stable dosage forms. Antioxidants are commonly used in formulation to alleviate the oxidation problem but they do not always achieve the desired results. In this study, a case of antioxidant-accelerated oxidation degradation in formulation is reported. The oxidation mechanism of a development drug candidate (1S,2S)-1-(4-hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidino)-1-propanol (1) in solution was investigated under various oxidative conditions, which include at different oxygen level, with transition metal ion spiking, and under light exposure with presence of photosensitizer. Oxidative degradation products and kinetics were monitored by high-performance liquid chromatography (HPLC). Kinetic solvent isotope effects of I oxidation in formulation, under metal ion catalysis, and upon photocatalysis were obtained. Metal ion spiking, exposure to stainless steel, as well as introduction of antioxidants such as ascorbic acid, thioglycerol, and sodium bisulfate, accelerated the oxidative degradation. Treatment of the solution with metal chelating resin inhibited oxidation. Kinetic solvent isotope effects are in agreement with a metal-catalyzed oxidation mechanism and inconsistent with a singlet oxygen pathway. On the basis of kinetic data, an oxidative fragmentation mechanism initiated by a metal ion catalyzed active oxygen species is suggested as the primary pathway for the oxidative degradation of I. Other oxidative species may be implied in the long-term oxidative degradation. Because many antioxidants act as pro-oxidants in metal-catalyzed oxidation, controlling metal ion contamination level in the excipients and limiting available molecular oxygen are recommended for formulation development.