Proton conducting ionomers are widely used for electrochemical applications including fuel-cell devices, flow batteries, and solar-fuels generators. For most applications the presence of interfacial interactions can affect the structure and properties of ionomers. Nafion is the most widely used ionomer for electrochemical applications due to their remarkable proton conductivity and stability. While Nafion membranes have been widely studied, the behavior and morphology of this ionomer under operating conditions when confined to a thin-film morphology are still not well understood. Using in situ grazing-incidence small-angle X-ray scattering (GISAXS) techniques, this work demonstrates that the wetting interaction in thin-film interfaces can drastically affect the internal morphology of ionomers and in turn modify its transport properties. Thin films cast on hydrophobic substrates result in parallel orientation of ionomer channels that retard the absorption of water from humidified environments; while films prepared on SiO2 result in isotropic orientation of these domains, thus favoring water sorption and swelling of the polymer. Furthermore, the results presented in this paper demonstrate that upon thermal annealing of Nafion thin films static crystalline domains form within the polymer matrix that restrict further water uptake. The results presented in this study can aid in the rational design of functional composite materials used in fuel-cell catalyst layers and solar-fuels devices.