Single-atom catalysts (SACs) often exhibit dynamic responses to the reaction and pretreatment environment that affect their activity. The lack of understanding of these behaviors hinders the development of effective, stable SACs, and makes their investigations rather difficult. Here we report a reduction–oxidation cycle that induces nearly 5-fold activity enhancement on Pt/TiO₂ SACs for the reverse water–gas shift (rWGS) reaction. We combine microscopy (STEM) and spectroscopy (XAS and IR) studies with kinetic measurements, to convincingly show that the low activity on the fresh SAC is a result of limited accessibility of Pt single atoms (Pt₁) due to high Pt–O coordination. The reduction step mobilizes Pt₁, forming small, amorphous, and unstable Pt aggregates. The reoxidation step redisperses Pt into Pt₁, but in a new, less O-coordinated chemical environment that makes the single metal atoms more accessible and, consequently, more active. After the cycle, the SAC exhibits superior rWGS activity to nonatomically dispersed Pt/TiO₂. During the rWGS, the activated Pt₁ experience slow deactivation, but can be reactivated by mild oxidation. This work demonstrates a clear picture of how the structural evolution of Pt/TiO₂ SACs leads to ultimate catalytic efficiency, offering desired understanding on the rarely explored dynamic chemical environment of supported single metal atoms and its catalytic consequences.