The degradation of lithospermic acid B (LAB) was investigated as a function of buffer concentration, pH and temperature. Stability tests were performed using a stability-indicating high-performance liquid chromatography (HPLC) with UV–vis detection. The degradation followed pseudo-first-order kinetics under all experimental conditions. The maximum stability of LAB was observed at pH 2.0. The logk_pH–pH profile described by specific acid–base catalysis and water molecules agreed with the experimental results. The overall degradation rate constant as a function of the temperature under the given conditions obeyed the Arrhenius equation. The chemical fate of LAB in mild acidic solution was investigated, and nine degradation products were detected and tentatively identified by LC–MS analysis. The primary degradation pathway involving the cleavage of ester bond and ring-opened of benzofuran in the LAB are proposed.