Fuel cell powertrains have higher efficiencies compared to internal combustion engine powertrains, but—despite lower thermal losses—thermal requirements are noticeably higher. The commonly used Polymer Electrolyte Membrane Fuel Cell is highly sensitive to temperature deviations; hence specifications of coolant temperatures must be strictly observed. Furthermore, their working-temperature level is closer to ambient air, requiring a more efficient cooling system. This work focuses on medium-duty and heavy-duty truck segments. The aim is to provide a possible optimization guideline for cooling system developers to select an adequate heat exchanger for available air mass flows. This energetical and thermal layout process is based on fuel cell module information provided by Plastic Omnium New Energies Wels GmbH, firstly by simple steady-state calculations and secondly by transient vehicle system simulations. To define the system to the full extent, the analyses cover full-load operation, VECTO cycles, real-driving cycles, and the highest ambient temperatures. Finally, an optimized system is presented, matching the best trade-off between heat exchanger size and mass flows. Results show a linear and then exponential increase in heat exchanger size with soaring thermal requirements. Thus, with a well-defined thermal layout validated on the full vehicle level, the lowest possible component sizes are identified at which still harshest mission profiles can be completed.