Biodegradable Zn-based composites have been recognized as a promising approach to develop the new generation biodegradable materials for orthopedic applications. However, the insufficient interfacial bonding between the Zn matrix and reinforcements limited the performance of Zn-based biocomposites. In this study, Cu2O modified graphene oxide (Cu2O-GO) sheets were employed as reinforcement to manufacture Cu2O-GO/Zn biocomposites via spark plasma sintering (SPS) process. Due to the low Gibbs free energy in the formation of ZnO (−163.8 kJ·mol−1), an in situ reaction between Cu2O and Zn matrix occurred during the SPS process, resulting in Cu and ZnO as reaction products. In the meantime, the Zn matrix could alloy with the in situ generated Cu, contributing to a Zn-Cu alloy matrix with enhanced mechanical performance. In other words, ZnO modified GO sheets reinforcing Zn-Cu matrix biocomposites were achieved by a one-step process. Intimate and strong interfacial connections between the graphene and Zn-Cu matrix were achieved in 4Cu2O-GO/Zn biocomposites via ZnO-related and CuZn4-related interfacial bonding. Considerable strengthening efficiencies (13.9–27.9) were confirmed in Cu2O-GO/Zn biocomposites. As a result, 4Cu2O-GO/Zn biocomposites exhibited a yield strength (YS) of 222.9 MPa, a degradation rate of 68.4 mm·y−1, acceptable cytocompatibility to MC3T3-E1 cells, and antibacterial activity of 98.6% to S. aureus.