This paper investigated the physical properties and vacancy formation of face-centered cubic (FCC) Co–Ni–Cu–Mo–W high-entropy alloys (HEAs) using first-principle calculation. Firstly, we analyzed the effect of W and Cu content on the physical properties of alloys. The calculation results show that increasing W content increased the thermodynamic stability, dislocation-energy factor and dislocation width of Co–Ni–Cu–Mo–W HEAs. The fracture energy increased with increasing W atoms at the fracture interface. However, the coefficient of thermal expansion of HEAs decreased with increasing W content. The effect of Cu on the physical properties of Co–Ni–Cu–Mo–W HEAs was contrary to that of the W element. Secondly, we investigated the effect of neighboring atoms on vacancy formation energy (Evf) of Co–Ni–Cu–Mo–W alloys. The results show that the Evf increased with more first-neighboring W and Mo atoms, and the Evf decreased with more first-neighboring Cu atoms. Lastly, we investigated the partial electronic density of state (PDOS) of the first-neighboring atoms before and after forming vacancy. The PDOS in sites with higher Evf changed more obviously after forming vacancy compared with the sites with lower Evf, which indicate that the atoms at higher Evf site have strong bonding effect with neighboring atoms.