The features of phase formation in Ni–Cr and Ni–Mo solid solutions during interaction of the components of Ni–20 wt% Cr and Ni–20 wt% Mo powder mixtures by high-temperature vacuum treatment and mechanical alloying were investigated. During high-temperature treatment, FCC nickel-based solid solutions formed due to diffusion of chromium or molybdenum into the nickel lattice. Diffusion interaction started at 1000°C and completed at 1200°C with formation of homogeneous Ni–Cr or Ni–Mo solid solutions. Mechanical alloying behavior strongly depended on the alloying element. Homogeneous FCC Ni–20 wt% Cr solid solution powder with a particle size of 50–100 μm was obtained after 15 h of low-energy milling in a Pulverisette 6 planetary mill. In contrast, complete homogenization of the Ni–20 wt% Mo system was not achieved even after 60 h of milling. The obtained results demonstrate that mechanical alloying is more efficient for Ni–Cr powders, whereas high-temperature vacuum synthesis is more suitable for obtaining homogeneous Ni–Mo solid solutions.