The search for highly active and selective catalysts with high precious metal atom utilization efficiency has attracted increasing interest in both the fundamental synthesis of materials and important industrial reactions. Here, we report the synthesis of Pd-Cu nanocubes with a Cu core and an ordered B2 intermetallic CuPd shell with controllable atomic layers on the surface (denoted as Cu/B2 CuPd), which can efficiently and robustly catalyze the selective hydrogenation of acetylene (C2H2) to ethylene (C2H4) under mild conditions. The optimized Cu/B2 CuPd with a Pd loading of 9.5 at. % exhibited outstanding performance in the C2H2 semi-hydrogenation with 100% C2H2 conversion and 95.2% C2H4 selectivity at 90 °C. We attributed this outstanding performance to the core/shell structure with a high surface density of active Pd sites isolated by Cu in the B2 intermetallic matrix, representing a structural motif of single-atom alloys (SAAs) on the surface. The combined experimental and computational studies further revealed that the electronic states of Pd and Cu are modulated by SAAs from the synergistic effect between Pd and Cu, leading to enhanced performance compared with pristine Pd and Cu catalysts. This study provides a new synthetic methodology for making single-atom catalysts with high precious metal atom utilization efficiency, enabling simultaneous tuning of both geometric and electronic structures of Pd active sites for enhanced catalysis.