Here, first-principles calculations were employed to study the properties of the W/Y2O3 interface and its effect on H dissolution and migration. Two W/Y2O3 interface structures were selected to investigate the influence of terminal structures and stacking sequences on the interface properties. The Y4O6–W (bridge) and O–W type A terminal interface exhibited the lowest interface energy at the W (110)/Y2O3 (222) interface with the orientation of W (1-10) ()/Y2O3 (2-1-1) () and at the W (200)/Y2O3 (400) interface with the orientation of W (001) (3 × 3)/Y2O3 (001) (1 × 1). The work of adhesion of the O–W type terminal interface is larger than those of the Y–W type and YnOm–W terminal interfaces, indicating that the O–W type A terminal interface has the most stable structure. Atomic-bonding analysis confirmed that the W–O bond plays an essential role in stabilizing the interface structure, and the stability improves as the density of the W–O bonds at the interface increases. These conclusions are further verified by charge-density difference calculations, which revealed that strong ionic bonds are formed between the W and O atoms at the W/Y2O3 interface. With regard to the H behavior at the W (200)/Y2O3 (400) interface, the segregation energy confirmed that the interface plays an important role in the segregation of H. The migration energy barrier of interstitial H along the interface is greater than that in the bulk. This means that the interface retains a significant number of injected H atoms, leading to an increase in the local concentration of H atoms at the interface. These results provide theoretical insights into the profound understanding of the interface properties and its effect on H behavior in Y2O3-dispersion-strengthened W.