A comprehensive study of advanced oxidation was conducted over Co-Cu layered double hydroxide (LDH) catalysts, while the Co-Cu interaction mechanism as well as oxygen vacancies (Ov) on the production of hydroxyl radicals (•OH) were studied systemically using LRS, UV-Vis, XPS, EIS and kinetics. Cu replacing Co sites in octahedral environment in α-Co(OH)2 could promote the oxidation of Co2+ by depressing the formation of β-Co(OH)2. A Co4Cu1 LDH catalyst showed the highest sulfadiazine (SDZ) removal efficiency of 93.7% from waste waters. The reaction mechanism was assumed on the base of kinetics study of SDZ removal. The formation of Co-O-Cu oxo-bridge in MO6 surroundings can enhance the generation of ameliorated Ov, which improves the formation of surface hydroxyl for H2O2 adsorption by boosting electron-transfer rate under the Co-Cu interaction. This study paves a new way to the Fenton-Like catalysts R&D, especially, orientating to the creation of active sites by vacancy engineering.