He–Xe, with a 40 g/mol molar mass, is considered one of the most promising working media in a space-confined Brayton cycle. The thermodynamic performance of He–Xe in different configuration channels is investigated in this paper to provide a basis for the optimal design of printed circuit board plate heat exchanger (PCHE). In this paper, the factors affecting the temperature distribution of the He–Xe flow field are analyzed based on the flow heat transfer mechanism. It is found that the flow patterns in the logarithmic and outer zones determine the temperature distribution pattern of the flow field. A series of numerical simulations verify the above conclusions, and it is found that reasonable channel structure and operating conditions can significantly improve the thermodynamic performance of the He–Xe flow. Based on the above findings, the Zig channel is optimized, obtaining Sine and Serpentine channels with different structural characteristics. Comprehensive thermodynamic comparisons of the helium–xenon flow domains inside channels are performed, and the Serpentine channel with a shape factor of tan 52.5° is found with the best performance. This work aims to improve the understanding of the thermodynamic performance of He–Xe in microchannels and provide theoretical support for further optimization of PCHE employing He–Xe.