The popularization of silicon transistor technology has arisen because of the high‐quality native oxide passivation of the silicon surface. The high‐k oxide solution to the continuous scaling of the devices is another technology milestone. In the new era of More Moore and More than Moore, 2D semiconductor alternatives as the channel materials are of considerable interest. Major 2D candidates, however, have not demonstrated thermally induced semiconductor/native oxide interfaces, analogous to Si:SiO2, for workable devices. Recently, a prototype 2D transistor based on a native oxide high‐k stack was showcased. The transistor is based on Bi2O2Se, an emerging layered 2D semiconductor, with its native high‐k oxide, Bi2O5Se, grown by thermal oxidation. This holds great promise for the development of 2D electronics. Here, comprehensive first‐principles investigations are carried out on the fundamental electrical properties of the native oxygen and selenium vacancies in Bi2O5Se, and two other less explored oxidized forms of Bi2O2Se, i.e., Bi2O9Se3 and Bi2O10Se3, which are found to have comparable bandgap values to that of Bi2O5Se. The corresponding vacancy defect landscapes are provided as an important guideline for the developmental applications of the Bi2O2Se:Bi2OxSey stack, as a 2D analogue of Si:SiO2.