In the process of underground resource extraction, deep rock masses are often subjected to cyclic-heating and water-cooling effects, which cause significant damage to the mechanical properties of rocks. In order to study the degradation mechanism of sandstone under cyclic heating and water cooling, many fracture experiments have been carried out. The effect of cyclic heating and water cooling at 200 °C on the tensile strength and the mixed-mode I-II fracture toughness of sandstone was investigated. The similarities and differences in the rock fracture characteristics and deterioration response of tensile properties are also examined. Meanwhile, the correlation between the microstructure and macroscopic fracture mechanical properties was revealed by observing the evolutionary pattern of rock microstructure. The findings demonstrate that the heating and water-cooling-induced variations in the tensile strength and fracture toughness of rock exhibit a consistent trend. The effective fracture toughness of sandstone decreases exponentially with increasing cycle times. The impact of the heating and water-cooling cycles on the fracture toughness of pure mode I is found to be more pronounced compared to that observed in mixed modes and pure mode II specimens. The failure mode of the rock sample undergoes a transition from abrupt to gradual, accompanied by an augmented development of cracks on the failure surface and finer fragmentation of rock debris. The results of this study can provide theoretical references for engineering practices such as the exploitation of geothermal resources and hydraulic fracturing.