Diffusion barrier materials (DBMs) are critical for the stability and efficiency of thermoelectric devices. Conventional DBM selection via density functional theory (DFT) calculations is computationally intensive. Here, we introduce an efficient screening approach that employs substitution energy as a surrogate for interfacial reaction energy, significantly reducing computational demand. By integrating substitution energy with migration energy barriers, we identify Ni as a robust DBM for Ag₂Se. Experimental validation confirms that Ni/Ag₂Se joints exhibit low contact resistivity (6.6 μΩ·cm²) and high thermal stability after 30 days of thermal aging. The Te-free Ag₂Se/MgAgSb devices achieve a maximum cooling temperature difference of 68 K at 350 K, comparable to state-of-the-art Ag₂Se/Bi₂Te₃ devices, while demonstrating excellent durability over 2000 power cycles. This strategy offers a rapid and reliable framework for DBM selection, accelerating the advancement of high-performance thermoelectric devices.