This work studied the degradation of pesticide thiamethoxam (TMX) by heat-activated and ultrasound-activated persulfate systems. The effect of different parameters on degradation in ultrapure water, such as initial pH (3–10), sodium persulfate (SPS) concentration (50−1000mg/L), TMX concentration (1−10mg/L), temperature (20−70°C) and ultrasound power density (20−42W/L) were examined. For the heat-activated system, TMX degradation increased with increasing temperature and SPS concentration and was favored at pH 6; the activation energy was computed at 108.7kJ/mol based on the Arrhenius law. Ultrasound alone was capable of partially degrading TMX, but the process was favored in the presence of SPS. For the ultrasound-activated system, degradation increased with increasing SPS concentration and power density at pH 6. The effect of temperature was controversial since the beneficial effect of high temperatures on SPS activation is offset by the reduced sonochemical activity due to the “cushioning” effect. Regardless of the activation system, the presence of chloride, bicarbonate and humic acid impeded TMX removal. Besides, TMX degradation was reduced in actual matrices, i.e. wastewater and bottled water, showing the competition between TMX and other matrix constituents for free radicals. For either system, mineralization was slower than TMX degradation, implying the formation of persistent by-products.