In chemical looping with oxygen uncoupling, oxygen carrier (OC) circulates between the fuel and air reactors to release and absorb O2 repeatedly. In order to assess the re-oxidation characteristic of Cu-based OC in the air reactor from the microscopic mechanism and macroscopic kinetics perspective, DFT calculations and isothermal oxidation experiments were conducted. In DFT calculations, Cu2O(111) surface was chosen as the objective surface to explore the oxygen uptake as well as the atomic transportation pathways, and to determine the rate-limiting steps basing on the energy barrier analyses. It was found that the energy barrier of the surface reaction step (0.96 eV) is smaller than that of the ions diffusion step (1.61 eV). Moreover, the Cu cations outward diffusion occurs more easily than O anions inward diffusion, which confirmed the epitaxial growth characteristic of Cu2O oxidation. The isothermal oxidation experiments were conducted in a thermogravimetric analyzer (TGA), and about 3.5 mg CuO@TiO2-Al2O3 particles within the diameter range of 75–110 µm were tested between 540 and 600 °C, where the internal and external gas diffusion effects were eliminated. Mixtures of 5.2-21.0 vol.% O2 in N2 were adopted as the gas agent for oxidation. Based on the understandings obtained from DFT calculations, a simple mathematical model with unknown parameters of the surface reaction process (mainly the activation energy, Ek) and ions diffusion process (mainly the activation energy, ED) was established to describe the overall oxidation process in TGA experiments. Eventually, these unknown parameters were determined as Ek = 50.5 kJ/mol and Ek = 79.2 kJ/mol via global optimization. With the attained parameters, simulations reproduced the experimental results very well, which demonstrated that this simplification model, where grain is converted almost layer by layer but different from the feature of the shrinking core model is able to accurately describe the overall oxidation process of Cu2O.