To achieve the goals of the peak carbon dioxide emissions and carbon neutral, the development and utilization of sustainable clean energy are extremely important. Hydrogen fuel cells are an important system for converting hydrogen energy into electrical energy. However, the slow hydrogen oxidation reaction (HOR) kinetics under alkaline conditions has limited its development. Therefore, elucidating the catalytic mechanism of HOR in acidic and alkaline media is of great significance for the construction of highly active and stable catalysts. In terms of practicality, Pt is still the primary choice for commercialization of fuel cells. On the above basis, we first introduced the hydrogen binding energy theory and bifunctional theory used to describe the HOR activity, as well as the pH dependence. After that, the rational design strategies of Pt-based HOR catalysts were systematically classified and summarized from the perspective of activity descriptors. In addition, we further emphasized the importance of theoretical simulations and in situ characterization in revealing the HOR mechanism, which is crucial for the rational design of catalysts. Moreover, the practical application of Pt-based HOR catalysts in fuel cells was also presented. In closing, the current challenges and future development directions of HOR catalysts were discussed. This review will provide a deep understanding for exploring the mechanism of highly efficient HOR catalysts and the development of fuel cells.