Understanding the behavior of solid-solid phase transformation in phase change materials is crucial to design advanced thermal energy storage materials. It is however challenging to study the complex solid-solid phase transition and predict the optimal composition with reliable performances (such as high energy storage at invariant phase transition temperature) in multi-component systems based on traditional empirical rules. Therefore, the high-throughput computational framework by coupling thermodynamic calculation via CALPHAD (CALculation of PHAse Diagrams) methodology with key experimental validation is firstly proposed for ternary Pentaglycerine-Tris-(hydroxymethyl)-aminomethane-2-amino-2-methyl-1,3-propanediol (PG-TRIS-AMPL) system. A self-consistent thermodynamic database of PG-TRIS-AMPL ternary system has been firstly assessed and validated by experimental measurements from in-situ X-Ray-Diffraction (XRD) and Differential Scanning Calorimetry (DSC). Using this thermodynamic database via CALPHAD method, the high-throughput calculation has been performed to seek the optimal composition in PG-TRIS-AMPL ternary system. It is found that two optimal ternary compositions in PG-TRIS-AMPL ternary system are designed as PG0.33TRIS0.07AMPL0.60 (ΔHmax = 137.5 kJ/kg) during the 1st invariant reaction αAMPL-rich+βPG-rich→δTRIS-rich+γAMPL-rich at 326.5 K (53.35 °C) and PG0.58TRIS0.069AMPL0.351 (ΔHmax = 52.44 kJ/kg) during the 2nd invariant reaction γAMPL-rich+βPG-rich→δTRIS-rich+γ’PG-rich at 338.4 K (65.25 °C), respectively. This finding shows the good balance between high latent heat storage and low invariant phase transition temperature at mid-temperature (20–100 °C) application. Also, the present high-throughput computation approach can be extended into other multicomponent systems for various temperature range.