Radioisotope thermoelectric generators (RTGs) have been widely used as a promising power source for space mission, in which the Multi-Mission RTG (MMRTG) is the state of the art type. However, due to the scarcity of the 238 P u fuel and associated cost concerns, there exists an imperative need to increase the efficiency of RTGs. This requires intuitive, detailed and accurate system property predictions of the RTG system. In this work, a comprehensive finite element model of the MMRTG has been developed, by using a commercial software, COMSOL Multiphysics, including a full-size three-dimensional geometry model, temperature dependent materials and the thermoelectric and radiation heat transfer multiphysics fields involved. The calculation results agree well with reported experimental and simulated values. Through the obtained detailed temperature and voltage distribution, thermal and power properties of the MMRTG are characterized and the effects of non-uniform distributions of temperature and power generated in each TE couple are revealed. At last, the parametric analyses of operation conditions, thermal environment and key design factors are performed and several salient findings have been obtained. Through the analysis results, the design parameters and working mechanisms of the MMRTG are clarified, which can help the design and optimization of the future hundred-watt RTG. • The comprehensive FEM method is first implemented in the MMRTG modeling and analysis. • The non-uniform distributions of temperature and power in TE modules are revealed. • Suitable load and sufficient thermal inventory ensure adequate power output. • The insensitivity of performance to ambient temperature expands MMRTG’s application.