As a critical electrochemical reaction region of the proton exchange membrane fuel cell (PEMFC), the cracking issue of the catalyst layer (CL) considerably affects the performance and durability of the PEMFC. However, the impact of chemical ionomer degradation on CL cracking has not been comprehensively revealed. This study investigates the effect of chemical ionomer degradation on CL cracking through accelerated stress tests, characterization, and theoretical analysis. The results indicate that the increasing chemical degradation degree facilitates CL cracking. The CL with the most severe chemical degradation has a single total crack length increment of 1.97 times for the novel CL under the same degree of mechanical degradation. CL fracture resistance analyses reveal that the decrease in interface fracture resistance is the predominant impulse in accelerating CL cracking. Furthermore, the cell voltage reduction of the CL with the most severe chemical degradation during mechanical degradation is 34.22 mV at the current density of 1800 mA cm−2, which is 1.82 times for the fresh CL. The increment of activation resistance and mass transfer resistance are the main causes of the larger cell performance loss. The above findings emphasize the significance of high interface fracture resistance in inhibiting CL cracking and offer theoretical support for analyzing post-operational CL cracking.