Temperature and chemical corrosion can strongly affect the micro and macro physical–mechanical properties of rocks. In order to study the effect of coupled thermal-chemical on mixed mode fracture characteristics of sandstone, many fracture tests were conducted with centrally cracked Brazilian disc specimens. Meanwhile, the mixedness (Me) and deterioration rate (ΔWij) were defined to quantify the responses of the effective fracture toughness (Keff), and the relation between Keff and Me was established. Finally, the surface photomicrographs and chemical reactions of sandstone were used to declare the essence of coupled thermal-chemical. The results show that the fracture toughness components (i.e.KIf, KIIf) and Keff have different decline degrees after undergoing thermal-chemical treatment, and the degradation degree of Keff is largest in acidic solution, followed by alkaline and neutral solution at the same temperature. In the case of same pH, the deterioration rate of Keff at 75 °C is about 1.2 to 1.5 times of 25 °C, and the influence of temperature is inferior to chemical corrosion. Furthermore, all kinds of physicochemical reactions are the direct reasons that weaken the physical and mechanical properties, because they change the microstructure and composition of sandstone. Moreover, the larger the loading angle or closer to the pure mode II loading condition, the reduction of Keff is more serious.