2D Ga2O3 nanosheet with ultra-high carrier mobility and wide bandgap has gained extensively interests due to its great potential in next generation of solar-bind photodetectors, high-power devices, and gas sensors. However, the study of the stability and air-resistance of Ga2O3 nanosheet is scare up to now. Herein, we investigate the stability and electronic properties of Ga2O3 in air through first-principles calculations. It is found that O2 molecule can physisorb on Ga2O3 nanosheet with the binding energy of −0.12 eV, while it is very hard to dissociate spontaneously due to an extremely high dissociation energy barrier of 4.78 eV. The O2 molecule physisorption can introduce extra energy levels in the bandgap and affect the optical properties of Ga2O3 nanosheet. While H2O molecule adsorption has weak effects on the structural and electronic properties of Ga2O3 nanosheet. The high air-resistance of Ga2O3 nanosheet is attributed to the strong charge transfer between the Ga and O ions, which avoids the surplus electrons induced by the dangling bonds to interact with foreign molecules. These theoretical results indicate Ga2O3 nanosheet has extremely high stability to resist oxidation and humid environment, which is a very promising next-generation 2D material for high-power and ultraviolet applications.