In this study, a magnetic copper ferrite/montmorillonite-k10 nanocomposite (CuFe2O4/MMT-k10) was successfully fabricated by a simple sol-gel combustion method and was characterised by X-ray diffraction (XRD), scanning electron microscopy (SEM), transmission electron microscopy (TEM), the Brunner–Emmett–Teller (BET) method, vibrating sample magnetometer (VSM), and X-ray photoelectron spectroscopy (XPS). For levofloxacin (LVF) degradation, CuFe2O4/MMT-k10 was utilized to activate persulfate (PS). Due to the relative high adsorption capacity of CuFe2O4/MMT-k10, the adsorption feature was considered an enhancement of LVF degradation. In addition, the response surface methodology (RSM) model was established with the parameters of pH, temperature, PS dosage, and CuFe2O4/MMT-k10 dosage as the independent variables to obtain the optimal response for LVF degradation. In cycle experiments, we identified the good stability and reusability of CuFe2O4/MMT-k10. We proposed a potential mechanism of CuFe2O4/MMT-k10 activating PS through free radical quenching tests and XPS analysis. These results reveal that CuFe2O4/MMT-k10 nanocomposite could activate the persulfate, which is an efficient technique for LVF degradation in water.