This study systematically investigates the influence of Ni interlayer thickness on the microstructure, mechanical properties, and corrosion resistance of Zr-4/Nb/Ni/316SS diffusion bonded joints. The experimental results reveal that the typical interface microstructure of the joints consists of Zr-4/β-(Zr, Nb)/Nb/Ni3Nb/Ni/316SS. The shear strength of the joints initially increases and subsequently decreases with increasing Ni interlayer thickness, reaching a peak value of 380 MPa at an interlayer thickness of 30 μm. To elucidate the effect of Ni interlayer thickness on the mechanical properties, the microstructural characteristics of the joint interfaces were characterized, and Abaqus simulations were conducted to analyze the residual stress distribution across the interfaces. The comparative analysis of the mechanical properties and fracture behavior, combined with simulation results, indicates that while thicker Ni interlayers are more effective in alleviating residual stress, excessively thick interlayers lead to a reduction in shear strength due to their enhanced ductility. Additionally, the corrosion resistance of the joints was assessed using full immersion corrosion tests. The results indicate that the corrosion rate decreases with a reduction in Ni interlayer thickness, with the optimum corrosion resistance observed at an interlayer thickness of 10 μm. In conclusion, it is recommended that the Ni interlayer thickness be maintained between 10 μm and 30 μm to achieve a balance between mechanical properties and corrosion resistance.