As a new energy technology, the fuel cell has developed rapidly, and its performance has been continuously improved. Fuel cell stacks composed of multiple single cells are gradually being used in portable electronic products. Since the performance of fuel cells cannot be optimal at room temperature, it is critical to research cell temperature characteristics and heat distributions in applications. In this paper, the effects of temperature and charge transfer coefficient and the relationship between exchange current density and output voltage were analyzed by the mathematical model of direct methanol fuel cells. Moreover, to optimize the thermal layout of the fuel cell stack in the printed circuit board (PCB) substrate, the idea of a fuel cell as a device was proposed innovatively, and the corresponding thermal optimization strategy was analyzed. A novel particle swarm optimization algorithm was used to detect the optimal layout of fuel cells of different specifications on the same substrate. The three-dimensional thermal simulation model was used to obtain the temperature data and verify the optimization results.