The efficiencies of the nanoscale zero-valent iron (nZVI) and hydrothermal and nZVI-heat activation of peroxydisulfate (PS) were studied for the decomposition of chloramphenicol (CAP) in aqueous solutions. The nZVI heat combined with activation of PS provided a significant synergistic effect. A central composite design (CCD) with response surface methodology (RSM) was employed to explore the influences of single parameter and interactions of selected variables (initial pH, PS concentration, nZVI and temperature) on degradation rates with the purpose of condition optimization. A quadratic model was established based on the experimental results with excellent correlation coefficients of 0.9908 and 0.9823 for R2 and R2adj. The optimized experimental condition for 97.12% CAP removal was predicted with the quadratic model as 15 mg/L, 0.5 mmol/L, 7.08 and 70 °C for nZVI dosage, PS, initial pH, and temperature, respectively. This study demonstrated the effectiveness of RSM for the modeling and prediction of CAP removal processes. In the optimal condition, Fe2O3 and Fe3O4 were the predominant solid products after reactions based on X-ray photoelectron spectroscopy (XPS) and X-ray diffraction (XRD) analysis, which could also act as the activators along with the reaction. Overall, it could be concluded that hydrothermal enhanced nZVI activation of PS was a promising and efficient choice for CAP degradation.