Abstract Kirkendall voids (KVs) at the Cu/Sn interface are a typical failure in integrated circuits, leading to solder joint cracking and electrical disconnection. Although the formation of KVs has been attributed to the difference in atomic diffusion rates at the Cu/Sn interface, the role of Cu intrinsic "quality" parameters (crystal defects) in this process remains unclear. This work systematically investigated the effects of Cu crystal defects on KVs: Cu substrates with different lattice defects and grain boundaries were prepared using proprietary electrodeposition additives, and the number of defects was quantitatively characterized by micro‐strain, geometric dislocation density, and geometric phase analysis. The thermal aging experiments further showed that the formation of intermetallic compounds and KVs was related to crystal defect energy. When the grain boundary energy was higher than the lattice energy, the additional driving force resulted in short‐circuit diffusion, causing local Cu depletion and voids. The low‐crystal‐defect samples maintained the local Cu/Sn interdiffusion equilibrium, resulting in fewer voids after 1000 h. This study emphasizes that regulating the crystal defects can reduce KVs and provides a new insight for improving the integrated solder joint’s reliability.