Diclofenac (DCF), one of the typically recalcitrant pharmaceuticals, has been frequently detected in groundwater in recent years. This work investigated the performance of DCF degradation by thermally activated persulfate (PS) to further understand its application in in situ chemical oxidation (ISCO) for DCF-contaminated groundwater. The effects of various factors, including activation temperature, solution pH, PS/DCF ratio, and common constitutes, e.g., HCO3(-), Cl(-) and humic acid, and the toxicity of transformation products were evaluated. The results indicated that the oxidation of DCF was well-fitted with a pseudo-first-order kinetic model, and the rate constants increased with the elevated temperatures. The rate constants from 50-70 °C were further fitted to the Arrhenius equation, yielding an activation energy of 157.63 kJ·mol(-1). In addition, the oxidation of DCF was highly pH-dependent, with the rate constants rapidly decreased from pH 5 to 7, then slightly increased at the alkaline pH. The presence of a low dosage of Cl(-)(0-10 mM) promoted the degradation of DCF, whereas high Cl(-) addition (>10 mM) inhibited DCF degradation. HCO3(-) exhibited a negligible effect on DCF removal, while natural organic matters, e.g., humic acids, lightly inhibited DCF degradation. The rapid degradation of DCF was also confirmed in the real groundwater sample, which might be attributed to the pH drop during the reaction. Moreover, the radical quenching experiments revealed that sulfate radicals (SO4·-)) was the dominant reactive species for DCF oxidation. Finally, the acute toxicity of the DCF solution, as tested with a bioluminescent assay, was gradually decreased during the reaction, indicating that a thermally activated PS oxidation was a promising alternative approach for DCF-contaminated groundwater remediation.