The development of welding technology for zirconium alloy has great significance on the safety, stability, and reliability of the operation of the nuclear reactor. In this work, vacuum diffusion bonding of Zr-4 alloy was studied at the diffusion temperature ranging from 760 to 820 °C with holding times of 30–90 min. The effects of diffusion bonding temperature and holding time on the interfacial microstructure and mechanical properties of the diffusion bonded Zr-4 alloy joints were investigated in detail, and the relationship between the interfacial microstructure and shear strength of the diffusion bonded joints was discussed. The results show that the interface bonding ratio of the diffusion bonded Zr-4 joint gradually increased from 74% to 95% with the increasing of bonding temperature. In addition, the grain size of the base material became a larger and brittle second phase composed of Zr(Cr, Fe)2 and eutectic α-Zr + Zr(Fe, Cr)2 formed in the joint with the increase of the temperature as well as the extension of the bonding time. The highest shear strength of 349 MPa was obtained at 800 °C for 30 min under 7 MPa, and the crack of the joint was primarily propagated along with the base material rather than the bonded interface.