With the help of photocatalyst materials, utilizing sunlight to split water and converting solar energy into hydrogen energy can not only solve the problem of environmental pollution, but also meet the needs of national strategies. Based on first-principles calculations, the present work has proposed two different configurations of two-dimension (2D) Janus In2SSeTe as photocatalysts for water splitting, named Model-I and Model-II, respectively. These two configurations of 2D Janus In2SSeTe show good lattice and thermal dynamics stability. It is found that Model-I is an indirect band gap semiconductor with a band gap value of 2.20 eV, while Model-II is a direct band gap semiconductor with a band gap value of 0.64 eV. Moreover, the intrinsic electric field in 2D Janus In2SSeTe can promote the spatial separation of photogenerated carriers to reduce carrier recombination, which is beneficial to photocatalytic applications. Furthermore, the suitable band edge positions and excellent light-harvesting ability suggest that the 2D Janus In2SSeTe is a very promising photocatalyst for water splitting. More importantly, under light radiation, the hydrogen evolution reaction (HER) and oxygen evolution reaction (OER) can occur spontaneously in the surface of Model-I configuration. These results will provide the theoretical foundation for the practical application of 2D Janus In2SSeTe in the field of photocatalytic water splitting.