Owing to high treatment efficiency under neutral condition and no extra energy required, copper-mediated activation of persulfate (PS) has been widely used for the degradation of refractory organic pollutants in water. The dispersion stability of copper nanoparticle in water, however, remains a great challenge. Meanwhile, chemical oxidative modification of graphene oxide (GO) can improve the dispersion stability of GO in water. In this paper, cuprous oxide (Cu2O) was deposited on the surface of GO. GO/Cu2O nano-composites with different mass ratios, i.e., m(GO):m(Cu2O) of 1:2, 1:5, 1:10, and 1:25, were prepared. When m(GO):m(Cu2O) was 1:2, the amount of GO/Cu2O nano-composite was 1.00 g/L and CPDS:CDCF was 15:1, and the catalytic degradation rate of diclofenac (DCF) was up to 90%. Corresponding physicochemical properties of the resulting samples were comprehensively characterized by using SEM, TEM, XRD, Raman, FT-IR, and XPS. DCF degradation by activating peroxydisulfate (PDS) via GO/Cu2O nano-composite was also investigated in detail. It is found that the synergistic effect, namely GO adsorption and multivalent copper ion electron transfer, makes GO/Cu2O nano-composite reveal higher reactivity. Moreover, GO/Cu2O nano-composite possesses good stability in consecutive cycling test. EPR analyses shows that ·OH and SO4·− radicals are involved in DCF degradation. It is indicated that the DCF degradation process contain hydroxylation and the cleavage of C-N bond, which is explored by GC–MS. In our research, well-dispersed GO/Cu2O nano-composite with high capacity and good cycling stability was fabricated successfully. Compared with pure Cu2O nanoparticle, GO/Cu2O nano-composite exhibits the better performance for DCF removal. A novel well-dispersed cuprous oxide (Cu2O) deposited on surface of GO was fabricated with high catalytic performance. Its heterogeneous activation of peroxydisulfate (PDS) for diclofenac (DCF) degradation was investigated. GO/Cu2O nano-composite was proved high capacity and good cycling stability. Meanwhile, the possible DCF degradation pathway was explored. Compared with pure Cu2O nanoparticle, GO/Cu2O nano-composite exhibits better performance for DCF removal. [ABSTRACT FROM AUTHOR]