Hexenuronic acid (HexA) not only influences delignification, but it is also one of the major factors producing absorbable organic halogens (AOX) during the chlorine dioxide bleaching of pulps. The efficient removal of the HexA from cooked pulp is important to minimize the need for bleaching and the pollution load from the mill effluent. Response surface analysis (RSA) was applied to determine the optimal oxidative degradation conditions for HexA in bagasse pulp. Based on the previous single-variable test results, reaction temperature, pH, and reaction time were chosen as the independent variables, with the amount of degradation of HexA being the response value in the RSA. According to the central composite experimental design principles, the type of response surface methodology with three factors and three levels was adopted and analyzed to determine the significant factors and the strength of interactions between factors. The optimal conditions determined were as follows: a reaction temperature of 94.7 °C, a pH of 3.7, and a reaction time of 124 min, which resulted in the amount of degradation of HexA at 10.5 µmol/g.