Improving the oxidation resistance of TiAl-based alloys at high temperature has great significance for expanding their application fields. Adding ternary and quaternary elements is one of the effective ways to solve the oxidation problem of this kind of alloys materials. The first-principles method based on density functional theory was used to study the Si and Y substitution co-doping effects on the oxidation resistance of γ-TiAl based alloys from the aspects of atomic average formation energy and elastic constant of system, as well as the formation energies of interstitial O atom, Ti vacancy and Al vacancy in the system. The results indicate that the atomic average formation energies of the Si and Y dual-doped systems are all negative, which imply they possess energy stability and can be prepared by experiments. In addition, the elastic constants of most Si and Y substitution co-doping γ-TiAl systems satisfy the mechanical stability criterion. For the mechanical stable systems, the analysis results about the formation energies of the interstitial O atom, Ti vacancy and Al vacancy reveal that the Ti₆SiYAl₈ series, in which both Si and Y substitute Ti, have obvious promotion effect on the improvement about oxidation resistance; system Ti₇YAl₇Si, in which Y substitutes Ti and Si substitutes Al, and system Ti₇SiAl₇Y, in which Si substitutes Ti and Y substitutes Al, have uncertain influence on improving oxidation resistance; system Ti₈Al₆SiY, in which both Si and Y substitute Al, is harmful to the improvement about oxidation resistance of the γ-TiAl based alloys. Therefore, the preparation conditions should be controlled moderately so that both Si and Y substitute Ti at the same time to form a large proportion configurations of Ti₆SiYAl₈ series in the materials. In these configurations, the outward diffusion of Ti atoms and the inward diffusion of interstitial O atoms are suppressed, meanwhile the outward diffusion of the Al atoms is facilitated. In this way, the production of α-Al₂O₃ is promoted and that of TiO₂ is weakened on the surface of co-doping γ-TiAl based alloys. Thus, a scale rich in α-Al₂O₃, i. e., a continuous, dense, and protective oxide scale can be grown on the surface of Si and Y substitution co-doping γ-TiAl alloys.