In this paper, a fully coupled non-isothermal, electrochemical, and transport 3D model for a 10-cell PEMFC stack with coolant channels is constructed and implemented to examine and compare the influence factors to the stack performance. The first case to be considered is under different thermal operation conditions, including thermostatic, adiabatic, and heat exchange operation. The corresponding results show that a better uniformity and the largest stack output power density can be obtained under heat exchange operation. The other case is to compare the effects of heat transfer coefficients for different materials (ranging from 5 W/(m2 ) to 50 W/(m2 )) on the spatial non-homogeneity of stack voltage and output power density. Numerical results indicate that the degree of the non-uniformity of individual cell voltage can be minimized, and the output power density can be elevated to a certain degree when the heat transfer coefficient is set as 25 W/(m2 ). In addition, an attempt is carried out to investigate the changes of some important variables due to the tolerance stacking or performance degradation, where we assume some cells’ contact resistance increases. We observe that a large jump of cell voltage and temperature occurs, which can be used as a detection signal for stack safety operation.