<p>Cu-Ni-Sn alloys serve as an eco-friendly alternative to toxic Cu-Be alloys, owing to their high strength, good wear/corrosion resistance, and excellent anti-stress relaxation properties. However, severe Sn segregation and discontinuous <i>γ</i>-DO₃ phase formation degrade their comprehensive performance, thereby hindering industrial application. Microalloying effectively mitigates these microstructural deficiencies, but the experimental optimization of multicomponent systems is time-consuming and costly, highlighting the urgent need for predictive thermodynamic models. In this study, the microalloying effects in Cu-Ni-Sn alloy were predicted using thermodynamic modeling combing Miedema model, Toop model, and Srikanth equation. Calculations of formation enthalpy indicated that Ti, P, Mg, Ca, Zr, Sr, and rare earth elements (REs) facilitate the formation of beneficial intermetallic compounds with matrix elements, thereby refining the microstructure and improving mechanical properties. Activity coefficient analysis showed that Ca, Sr, Ba, Zr, and REs suppress Sn segregation by lowering Sn activity. Detailed analysis of activity coefficient differences between Cu/Ni and Sn components at 673&#xa0;K revealed that Ti, Al, P, Mg, Sc, Zn, and Zr significantly retard the nucleation and growth of both Cu₃Sn and Ni₃Sn phases, among which P exhibits the strongest inhibitory effect. These findings provide critical theoretical guidance for optimizing microalloying strategies in Cu-Ni-Sn alloys.</p>