Dysfunction of the hippocampal formation is thought to contribute to major depressive disorder, but the role of the entorhinal cortex (Ent) is unknown. Here, molecular and chemogenetic approaches were used to selectively excite Ent→dentate gyrus (DG) projections. Compared with controls, these mice showed increased hippocampal neurogenesis and antidepressive-like behaviour in models of depression and chronic stress, effects that were lost when neurogenesis was ablated by X-ray irradiation, suggesting that they are neurogenesis-dependent.