Abstract: The oxygen initiation process, one of the key processes in the early stage of the autothermic pyrolysis in-situ conversion technology, has not been deeply investigated, which seriously limits its development. In this study, the reaction behaviors, kinetic parameters, heat and product release characteristics during the isothermal oxygen initiation process of Huadian oil shale in O2/N2 mixtures with different oxygen concentrations and initiation temperatures were investigated via TG/DSC-FTIR. The results show that the samples exhibit three different reaction behaviors during the initiation stage, consisting of two main parts, i.e., the oxidative weight-gain and the oxidative reaction phases. The former phase is mainly characterized by the oxygen addition reaction that produces oxidizing groups which increase the sample mass. And the latter stage consists of two main subreactions. The first subreaction involves the oxidative cracking and pyrolysis of oxidizing groups and kerogen to produce fuel deposits such as residual carbon, while the second subreaction focuses on the oxidation of the resulting fuels. Furthermore, increasing the oxygen concentration significantly promotes the above reactions, leading to an increase in the reaction intensity and reaction rate. Owing to the combined effect of oxygen concentration and residual organic matter content, the total heat release increases with the increasing initiation temperature and reaches its maximum at 330–370 °C. In addition, the preheating stage primarily produces hydrocarbon gases, while the initiation stage predominantly generates CO2. As the preheating temperature increases, the CO2 output intensifies, the required reaction time shortens, and the release becomes more concentrated. Based on these findings, a reaction mechanism for the oxygen initiation process of Huadian oil shale was proposed, and recommendations were provided for optimizing the construction process.