Mechanisms and dynamics of thermo-oxidative degradation of styrene-co-isoprene (SI) diblock at a temperature above the order–disorder transition temperature, Todt, have been investigated both experimentally and theoretically. The structural development of SI during degradation was monitored by optical microscopy, and the reduction of molecular weight and molecular weight distribution during the degradation was determined by gel permeation chromatography (GPC). The degradation process was modeled in the framework of a kinetic model based on the framework of the Flory principle. The theoretical predictions were compared with the GPC results. Fourier transformed infrared spectroscopy (FTIR) experiment was conducted in situ during the thermo-oxidative degradation of the SI copolymers, to gain further insight into the chemical modification mechanisms, the reduction of unsaturated double bonds and the formation of carbonyl and hydroxyl groups.