In the recent years, the urgency to decarbonize the mobility sector has highlighted the importance of the electrochemical hydrogen use in fuel cells to complement the battery-based electrification. Hydrogen is the greenest energy carrier, and low-temperature Polymer Electrolyte Membrane Fuel Cells (PEMFCs) are part of an ever-evolving scenario, with particularly promising use in high energy demand sectors. Hydrogen is the main player in decarbonisation scenarios, but there are many issues, including its production and storage. There are many categories of hydrogen; in these applications, the finest category of hydrogen, called green hydrogen, is required. To achieve completely green vehicle mobility, enormous technological advances are necessary. This paper presents a 3D-CFD study to analyse the behaviour of PEMFCs by examining the role of humidification, covering fully humidified (anode and cathode), anode-only, cathode-only, and fully dry operations. This is simulated for several membrane thicknesses, reproducing a wide matrix of operating conditions and separator choices, and examining their respective effect on the cell’s resistance. The obtained results confirm that the fully dry operation results in a significant increase in cell’s internal resistance, as well as the opposite is verified for fully humidified operation. However, maintaining an external anode-only humidification and relying on the internal self-humidification can be a highly effective strategy, allowing to reduce the complexity of the balance of plant by simplifying the humidifiers sub-system. This is analysed in conjunction with the effect of the electrolyte thickness, which opens to the possibility to enhance or even suppress self-humidification and water transport. Conclusions provide an overview of the design and operating choices to minimize the cell’s resistance at a minimum system complexity cost.