Within the framework of Urusov’s crystal energy theory of isomorphous substitutions, the mixing energies (interaction parameters) in (Y1–xLnx)2SiO5 systems, where Ln represents rare-earth elements (REEs), have been calculated. It has been demonstrated that the mixing energy during the substitution of yttrium by REEs from the cerium subgroup is determined mainly by the size differences of the substituting structural units. At the same time, the yttrium subgroup is primarily influenced by the differences in the degree of ionicity of the chemical bonds of the system's components. The solid solutions’ decomposition (stability) temperatures were calculated, and based on these, thermodynamic stability diagrams for all systems and decomposition domes for each system were constructed. These diagrams allow for predicting the equilibrium substitution limits (x) as a function of temperature or the decomposition temperature based on specified substitution limits and the areas of thermodynamic stability. The results of this work can help choose the component ratios in matrices and the amount of activator (dopant) in new luminescent, scintillation, and other materials based on REEs oxyorthosilicate solid solutions of the composition (Y1–xLnx)2SiO5 with the space group P21/c.