Hydrogen-fueled fuel cells are considered one of the key strategies to tackle the achievement of fully-sustainable mobility. The transportation sector is paying significant attention to the development and industrialization of proton exchange membrane fuel cells (PEMFC) to be introduced alongside batteries, reaching the goal of complete de-carbonization. In this paper a multi-phase, multi-component, and non-isothermal 3D-CFD model is presented to simulate the fluid, heat, and charge transport processes developing inside a hydrogen/air PEMFC with a serpentine-type gas distributor. Model results are compared against experimental data in terms of polarization and power density curves, including an improved formulation of exchange current density at the cathode catalyst layer, improving the simulation results’ accuracy in the activation-dominated region. Then, 3D-CFD fields of reactants’ delivery to the active electrochemical surface, reaction rates, temperature distributions, and liquid water formation are analyzed, and critical aspects of the current design are commented, i.e., the inhomogeneous use of the active surface for reactions, limiting the produced current and inducing gradients in thermal and reaction rate distribution. The study shows how a complete multi-dimensional framework for physical and chemical processes of PEMFC can be used to understand limiting processes and to guide future development.