• We study He interacting with 27 substitutional solutes in vanadium. • Early three 3 d /4 d /5 d substitutional solutes can attract He atoms for each period. • Sc, Ti, Y, and La can significantly reduce the He diffusivity. • We determine synergistic interactions of He, substitutional solute and vacancy. We systemically investigated helium (He) interacting with 27 substitutional solute elements in vanadium by first-principles calculations. The interactions between early three 3 d /4 d /5 d transition solutes and He are attractive while they are repulsive for other solute elements, He still favors tetrahedral sites. We predicted the influence of substitutional solutes on He effective diffusivity, Sc/Ti/Y/La can obviously reduce He diffusivity while other solutes show little effect. Moreover, we studied the synergistic interactions of the defect complex with He, solute and vacancy. The binding of group IIIB/IVB solution elements and vacancy reduce vacancy capturing for He, inhibiting He clustering in vacancies. The presence of He increases the stability of solute–vacancy clusters. The results can help to understand the effect of solute elements on He accumulation and embrittlement in vanadium alloys under irradiation.