Inflammation is a crucial component that contributes to the pathogenesis of major depressive disorder. It has been revealed that the nonselective cation channel transient receptor potential vanilloid 4 (TRPV4) profoundly affects a variety of physiological processes, including inflammation. However, its roles and mechanisms in LPS-induced depression are still unclear. Here, for the first time, we found that there was a significant increase in TRPV4 in the hippocampus in a depression mouse model induced by LPS. TRPV4 inhibitor HC067047 or knockdown the hippocampal TRPV4 with TRPV4 shRNA could effectively rescue the aberrant behaviors. Furthermore, TRPV4 inhibitor HC067047 reduced the activation of astrocyte and microglia, decreased expression of CaMKII-NLRP3 inflammasome and increased the expression of neurogenesis marker DCX in the hippocampus. In addition, enhanced neuroinflammation in the serum was also reversed by TRPV4 inhibitor HC067047. Thus, we consider that TRPV4 has an important role in contributing to the depression-like behavior following LPS-induced systemic inflammation.