The High Temperature Polymer Electrolyte Fuel Cell (HT-PEMFC) stacks using polybenzimidazole (PBI) based membranes have an inability to internally heat up at low temperatures to their nominal operating temperature (160°C–180°C) during the start-up process. Several strategies, such as direct electrical heating, coolant/gas channel heating, catalytic hydrogen-oxygen combustion, etc., are proposed in the literature to assist the heating for quick start-up situations. However, little knowledge exists on the transient thermomechanical stresses induced during the start-up heating process due to non-uniformity in heat supply and disparity in thermal properties of the cell components. The objective of the present research is to analyze the thermal gradients and thermal stresses developed in the HT-PEMFC structure during the start-up with various heating methods discussed in the literature, as well as during the cell operation by exploiting the Fluid-Structure Interaction (FSI) approach. The use of polyalkylene glycol (Fragoltherm S-15-A) based Heat Transfer Fluid (HTF) in the coolant channel has substantially improved the start-up time due to the high Nusselt number. However, a significant gradient in temperature distribution is observed during the preheating process, which resulted in great inhomogeneous stresses in the membrane, particularly in the in-plane direction. Interestingly, the degree of uniformity in membrane current density distribution during cell operation is increased. A detailed heat analysis in the cell showed that the heat generated in the cell due to electrochemical reactions is sufficient to raise the cell temperature from 120°C to operating temperature in a short time. Being subjected to a compressive stress of above 40 MPa, which is higher than the ultimate strength of a typical acid doped PBI membrane, the electrolyte is the most vulnerable component during the start-up. Hence, to inhibit the concomitant effect on cell performance and degradation, a novel start-up strategy should be implemented.