Nowadays, Zinc (Zn)-based biocomposites as biodegradable implant materials have been recognized as a promising approach to overcome the insufficient mechanical performance of Zn matrix and to endow the Zn-based materials with biofunctionality. However, the strengthening effect on Zn-based matrix composite remains far from expectation mainly due to the poor interfacial bonding between the reinforcement and Zn matrix, and the relatively coarse grain size of the Zn matrix. Herein, we have developed a novel in situ wetting strategy to ameliorate the interfacial bonding and mechanical performance of Zn-Ag-based composites using cuprous oxide-modified graphene oxide (Cu2O-GO) sheets as reinforcement. The enhanced interfacial bonding between GO sheets and Zn matrix owing to the in situ generated ZnO interlayer and the ultrafine microstructure with an average grain size of 360 nm were simultaneously achieved in the hot extruded (HEed) 1 wt%Cu2O-GO/Zn-2 wt%Ag biocomposites. Consequently, HEed biocomposites possessed excellent tensile properties, including ultimate tensile strength (UTS) of 344.0 ± 2.4 MPa, yield stress (YS) of 314.0 ± 4.8 MPa, and elongation at failure of 15.5% ± 1.3%. Ultrafine and uniform microstructure of the HEed biocomposites resulted in a relatively uniform corrosion morphology and a degradation rate of 0.195 ± 0.004 mm y−1 in simulated body fluid (SBF) solution. The 2-fold diluted extract of the HEed biocomposites exhibited satisfying cytocompatibility with MC3T3-E1 pre-osteoblast comparable to that of Ti-6Al-4 V ELI alloys. More importantly, the synergistic effect of metallic ions, Ag-rich nanoparticles, and GO sheets contributed to the remarkable antibacterial activity of the experimental biocomposites against both S. aureus and E. coli. These results demonstrated that the 1Cu2O-GO/Zn-2Ag biocomposites should be anticipated as a promising biodegradable material for orthopedic applications.