It is critical to effectively eliminate recalcitrant organic pollutants from wastewater. In this paper, the MoSe2/SrTiO3 (MST) catalysts were synthesized through simply controlling the amount of MoSe2 in the hydrothermal method to activate peroxymonosulfate (PMS) for the degradation of pollutants. The results demonstrated that sulfamethoxazole and tetracycline were almost eliminated by PMS/MST-3 (MoSe2/SrTiO3 mass ratio 0.3: 1) activation system. The effect of inorganic anions (Cl -, H2PO4 -, HCO3 -) and metal ions (Cu2+, Ni2+, Zn2+) commonly found in actual water bodies on catalytic reaction was explored. Moreover, SO4• -, •OH and 1O2 were identified by EPR tests and scavenger experiments, where the SO4• - and •OH were the dominant reactive species. The XPS analysis indicated that the oxygen vacancies and charge transfer on the catalyst surface were the keys of PMS activation. The effect of active sites in SMX and TC on the catalytic degradation activity was explored by density functional theory, and it was obtained that the central nitrogen site of SMX was more vulnerable in the catalytic system, while the edge oxygen site of TC was more susceptible to attack.