Coarsening of cuboidal γ′ precipitates and relevant diffusion process in Ni-based single-crystal superalloy CMSX-4 were investigated at 1000, 1020 and 1040 °C for specific times. The γ′ coarsening kinetics followed a cubic rate law with time and was presumably controlled by bulk diffusion of elements in γ matrix. The associated diffusion activation energy was experimentally determined to be about 300 kJ/mol when it is considered the temperature-dependent thermo-physical parameters in modified Lifshitz-Slyozov-Wagner theory. The influence of temperature on γ/γ′ microstructure is briefly discussed based on pseudo-binary [Ni]-[Al] phase diagram. Interactions among elements can effectively raise the local vacancy formation and vacancy-atom exchange barriers close to γ-and γ′-partitioning elements, respectively. Thus, it can significantly reduce the inter-coupling migrations of atoms during the macroscopic cross-diffusion process associated with γ′ coarsening of Nibased superalloys.