Refractory multi-principal element alloys (MPEAs) hold promise for next-generation plasma-facing materials, but their susceptibility to phase instability at intermediate temperatures (500–800°C) hinders their long-term use as structural nuclear materials. This study employed a CALPHAD (CALculation of PHAse Diagrams) approach to rationally design several novel non-equimolar TiVTa and Cr-doped TiVTa alloys with enhanced phase stability and discovered the phase stability of which at different temperatures. Differential scanning calorimetry (DSC) and x-ray diffraction (XRD) results confirmed the exceptional phase stability of Ti33V33Ta34, Ti29V28Ta43, Ti34V30Ta36 and Cr-doped TiVTa alloys, which retained a single BCC phase after heat treatment at 500°C and 700°C for 24 h. However, increasing Cr additions led to the precipitation of a Laves phase along grain boundaries within the vicinity of Ti-rich HCP phase region. This study demonstrates the power of integrating CALPHAD predictions with further experimental validation to accelerate the development of low-activation, high-temperature stable MPEAs for demanding applications.