The solute segregation and its effects on the cohesion of the Fe/Y₂Ti₂O₇ interface in ferritic oxide dispersion strengthened (ODS) alloy have been investigated using first-principles calculations. The computational results indicate that W, Cr, Al, Nb, Zr, and Hf are prone to segregate to the Fe/Y₂Ti₂O₇ interface and enhance the cohesive strength of the Fe/Y₂Ti₂O₇ interface, improving its stability. He atoms exhibit a strong tendency to segregate at the Fe/Y₂Ti₂O₇ interface, leading to embrittlement of the interface. Moreover, in the case of co-existing of W, Cr, Al, Nb, Zr, and Hf with He atoms, it is found that W, Cr, and Al increase the segregation energy of He at the Fe/Y₂Ti₂O₇ interface. This promotes the diffusion of He from the Fe/Y₂Ti₂O₇ interface into the bulk of the Y₂Ti₂O₇, thereby reducing He-induced embrittlement at the Fe/Y₂Ti₂O₇ interface. Finally, the electronic structures of the Fe/Y₂Ti₂O₇ interfaces with and without solute elements, as well as the interaction between metallic solutes and He, have been discussed in detail to reveal the mechanisms of alloying reduction effect on He-segregated embrittlement at the Fe/Y₂Ti₂O₇ interface. The results obtained from this work suggest that adjusting the alloying components in ODS alloys can improve the radiation resistance of the alloy, providing theoretical guidance for the design and optimization of ferritic ODS alloys.