A 100-W radioisotope thermoelectric generator (RTG) is by far the most suitable power supply for long-term deep space exploration where solar power would not be feasible. Understanding the thermal performance and electrical performance of the RTG under operational conditions is paramount for its nominal and safety performance during the space mission. In this paper, modeling and experimental studies on the thermal behavior and electrical performance of the 100-W RTG have been conducted. The RTG uses high conversion efficiency skutterudite-based thermoelectric convertor (TEC) arrays thermally coupled with a radioisotope heat unit (RHU) to generate electricity. A comprehensive finite element model and an electrical heating prototype of the 100-W RTG have been built to assess the performance of the RTG designs. Critical temperature, generated power, and energy conversion efficiency were evaluated. The simulation results show that the maximum output power of the RTG can reach about 120 W(electric); the temperature of the hot end of the TECs is about 853 K, and the temperature of the cold end is about 473 K, making a temperature difference of about 380 K. The RTG prototype with Bi2Te3 TECs generated about 60 W(electric) of electrical power in the first experimental research stage. These research results have significant reference for extension of the RTG prototype to the actual power source of the RHU and allow for future research and development improvements of the 100-W RTG.