With 12.7% power conversion efficiency and sustainable constituents, Cu2ZnSn(S1−xSex)4 (CZTSSe) is a next-generation photovoltaic front-runner. Going beyond requires maximizing two limiting parameters: open-circuit voltage and short-circuit current density. Doing so primarily necessitates synthesizing the single-phase of CZTSSe with minimal detrimental defects such as Cu–Zn and Sn–Zn antisite pairs (CuZn + SnZn, 2CuZn + SnZn) and S-vacancy (VS). Providing a framework that allows one to understand the thermodynamic limits on the single-phase stability and defect formation from the first-principles calculations, we determine that at least one anion-poor growth condition is needed to obtain the single-phase CZTSSe. Se-poor growth condition is found to be the optimal choice to this end, and Se-rich (Se/(S+Se) >0.5) alloy composition is likely to maximize the CZTSSe’s solar-to-current efficiency.