PEMWE is becoming one of the most promising technologies for efficient and green hydrogen production, while the anode OER process is deeply restricted by the now commercially used iridium oxide with sluggish reaction kinetics and super high cost. Deeply exploring the essential relationship between the underlying substrate materials and the performance of PEMWE cells while simultaneously excavating new practical and convenient methods to reduce costs and increase efficiency is full of challenges. Herein, two representative kinds of iridium oxide were studied, and their performance difference in PEMWE was precisely analyzed with electrochemical techniques and physical characterization and further linked to the ionomer/catalyst compound features. A novel anode with a uniform thin ionomer coating was successfully constructed, which simultaneously optimized the ionomer/catalyst aggregates as well as electrical conductivity, resulting in significantly enhanced PEMWE performance. This rigorous qualitative analysis of the structure–performance relationship as well as effective ionomer-affinitive optimization strategies are of great significance to the development of next-generation high-performance PEM water electrolyzers.