In this study, we investigated the stability of the W/Y2O3 interface and the behaviors of He near the interface using the first-principles method. We reported that the termination structures had an essential effect on interfacial stability by calculating the adhesion energy and interface energy. The OW-terminated interface had better stability than the YW-terminated interface when O chemical potential ΔμO was larger than − 5.1 eV. The result of the segregation energy demonstrated that the W/Y2O3 interface could act as a strong trap to capture the He of the W layer, but it was extremely difficult to capture the He of the YO layer. By examining the effect of strain on the dissolution property of He in W and Y2O3 bulks, we reported that the strain caused by lattice matching would be the primary reason to affect the solution of He near the interface. A diffusion study reported a reaction region in the W layer near the interface, the thickness approached 0.3 nm. The interface was favorable to the release of the He because the trapped He preferred to diffuse along the interface plane, rather than to be filtered in the W and YO layers across the interface. In addition, we also reported that the configuration of the He cluster at the interface roughly presented as a flat platelet structure and accommodated up to three He atomic layers. Those calculation results agreed with experimental results and provided theoretical support to deeply understand the phase interface effects on the behaviors of He in the Y2O3 dispersion strengthened W.