Non-radical activation of persulfate (PS) is a promising technology for removing organic pollutants in water because of the higher selectivity and stability of activated PS than radicals. Hence, the development of effective catalyst for PS non-radical activation is highly desired. In this work, a series of Mn doped CuO samples were prepared and used for removing ofloxacin with PS activation. The correlation between their surface properties and catalytic performance was studied, and the key parameter affecting pollutant degradation was explored. The result indicates that the CM3 sample (Cu:Mn = 6:1) exhibited the highest activity for ofloxacin degradation at neutral pH due to its high adsorption capacity towards ofloxacin and high activity for non-radical activation of PS, which is beneficial for their surface reaction. The large surface area and uncharged surface of CM3 at neutral pH facilitate the adsorption of ofloxacin, while its surface Cu2+ with less electron deficiency might be responsible for the production of activated PS. Because ofloxacin was mainly degraded by the activated PS, the common ions in real water had little effect on this process. The toxicity assessment indicates that the treated ofloxacin solution was harmless. Finally, the reusability experiment demonstrates that CM3 is a stable and effective catalyst for non-radical activation of PS.