Immune responses occurring in the central nervous system as a result of infection or exposure to toxins are referred to as neuroinflammation. It is heavily involved in the pathogenesis of neurodegenerative conditions of the brain. In the present study, we investigated the effects of a water extract of <i>Humulus japonicus</i> (HJW) on neuroinflammation and its fundamental mechanisms in lipopolysaccharide (LPS)-treated BV-2 murine microglial cells and in a mouse model. HJW inhibited LPS-induced secretion of nitric oxide, interleukin (IL)-6, and tumor necrosis factor-α (TNF-α), as well as the mRNA expression of <i>Il1b</i> in BV-2 cells. In the group co-administered with HJW, 24 h after LPS administration, a significant downregulation of <i>Il6</i> expression occurred in the cerebral cortex, as well as in TNF-α and IL-6 in the blood. In the group co-administered HJW, microglial activation was effectively suppressed in the cerebral cortex after 24 h of LPS injection and in the hippocampus after 24 h. LPS-induced elevation of phospho-p38 was significantly reduced by administration of HJW to the hippocampus of mice and to BV-2 cells. Furthermore, HJW effectively alleviated cognitive deficits induced by repeated LPS injections in a novel object recognition test. These findings suggest that HJW may offer therapeutic benefits as a natural extract for treating neuroinflammation, thereby enhancing memory and cognitive functions.