Oxidation of alumina-forming alloys and breakdown of a-Al2O3 are important processes for alloys used in hightemperature environments. By using density-functional theory simulations, we investigate the formation and diffusion of three common point defects. Influences of diffusion pathway, axial strain and alloy doping on defect energetics during its formation and diffusion are systematically investigated. Results indicate a positive correlation between the diffusion energy barrier and the pathway length. We highlighted that diffusion barrier of vacancy defects can be reduced to that of interstitial defects by applying tensile strain, indicating that the strain state can transform the diffusion mechanism within a-Al2O3 . Moreover, the alloying dopants (Cr, Mo, Cu, Si, Y, Zr) investigated here can be categorized as: inhibitive, promotive, and inert, depending on their roles in determining the diffusion barrier of oxygen vacancy, which is analyzed by the element-dependent substitution energies, atomic radius, electronegativity, volumetric change, and electronic transition.