Micro-structure related behavior of diffusion bonding joints is a crucial issue in device and reactor fabrication of Micro Chemo Mechanical Systems. However, the previous studies have been focused on the macro mechanical performance of diffusion bonded joint, especially diffusion bonding conditions effects on tensile strength, shearing strength and fatigue strength. The research of interfacial micro-voids and microstructures evolution for failure mechanism has not been carried out for diffusion-bonded joints. An interfacial electrical resistance measuring method is proposed to evaluate the quality of bonded joints and verified by using two-dimensional finite-element simulation. The influences of micro void geometry on increments of resistance are analyzed and the relationship between bonded area fraction and resistance increment is established by theoretical analysis combined with simulated results. Metallographic inspectons and micro-hardness testing are conducted near the interface of diffusion bonded joints. For the purpose of identifying the failure mechanisms of the joints, both microscopic tensile and fatigue tests are conducted on the self-developed in-situ microscopic fatigue testing system. Based on the microscopic observations, the mechanism of interfacial failure is addressed. The observation result shows that for 316LSS diffusion-bonded joints, microstructure evolution and effect of micro-voids play a key role in interfacial failure mechanism. Finally, a new life prediction model in terms of the increment of electrical resistance is developed and confirmed by the experimental results. The proposed study is initiated that constituted a primary interfacial failure mechanism on micron scale and provide the life prediction for reliability of components sealed by diffusion bonding.