This study studies the degradation of chlortetracycline hydrochloride CTC by activated peroxymonosulfate (PMS) with natural manganese sand NMS . Meanwhile, the NMS was characterized and analyzed by isothermal nitrogen adsorption (BET), X-ray energy spectroscopy (EDS) and scanning electron microscope (SEM). It can be induced that NMS material may contain C, O, Al, Si, Fe, Mn, K, and the proportion of each is 6%, 9%, 13%, 34%, 27%, 5%, 6%. Critical parameters, including initial pH value, catalyst dosage and PMS amount, were optimized through response surface methodology. Results indicated that 81.65% of CTC could be degraded under the optimized conditions of PMS amount 2.02g/L, the NMS dosage 0.29g/L and pH 3.87. Also, it shows that NMS is the most powerful of each factor on the degradation e ciency. We proposed the degradation pathways of CTC from the liquid chromatographmass spectrometer (LC-MS) results. Therefore, NMS could be applied as an e cient activator of peroxymonosulfate to purify the water and wastewater.