The mediation of vacancy in catalysts is crucial for the enhancement of oxidant activation. Here the boron nitride loaded with Co mixed oxides (Co2O3-CoO) and boron vacancy (Bv) catalyst (Co/BN-X) was prepared to degrade sulfamethoxazole (SMX) by activating peroxymonosulfate (PMS). Under dark condition, Co/BN-3+PMS system can completely remove SMX in surface water within 15min, and its removal efficiency constant (0.5154min-1) was 4.0 and 6.7 times greater than those of Co/BN-2+PMS (0.1284min-1) and Co/BN-1+PMS (0.0771min-1), respectively. The system showed excellent performance in different influencing factors and cyclic experiments, and exhibited good practical application potential in secondary effluent. Electron paramagnetic resonance, radical quenching and electrochemical tests certified that singlet oxygen (1O2) was the major active species, followed by •O2–, and SO4•–, further elaborating the activation pathway of PMS in Co/BN-3+PMS system. The density functional theory (DFT) calculations confirmed that CoO and PMS-O2 sites were the main reaction sites, and the existence of Bv reduced the adsorption energy of Co/BN-3 for PMS. This work reveals the synergistic effect between Co oxide sites and Bv on the catalyst surface and offers a potential modification method to accelerate Fenton-like reaction.