The pH is a critical factor determining the rate of the degradation of erythromycin A in aqueous solutions. However, the kinetics of the acid- and base-catalyzed degradation is still uncertain. This study used a sensitive coulometric detection method to determine concentrations of erythromycin A and its degradation products. To determine the buffer-independent rate constants, sodium acetate (0.05–0.2 M) and Tris–HCl (0.1–0.5 M) were used in a pH range of 3.5–5.5 and 7.0–9.0, respectively. In acidic conditions, anhydroerythromycin A appeared to be produced directly through an internal dehydration of erythromycin A-6,9-hemiketal which simultaneously established an equilibrium with erythromycin A enol ether on the other hand. In weakly alkaline conditions, hydroxide ion appeared to catalyze the hydrolysis of the lactonyl ester bond of erythromycin A-6,9-hemiketal by the pseudo-first-order kinetics, and the C13→C11 translactonization and internal dehydration reactions subsequently occurred to form pseudoerythromycin A enol ether. We suggest here a predictive model for reasonable interpretation of the kinetics of erythromycin A degradation in aqueous solutions, in which the observed rate constant was expressed by the sum of the partial reaction rate constants for the acid- and base-catalyzed degradation of erythromycin A-6,9-hemiketal as a function of pH in a range of 3.0–10.0.