Neuroinflammation has been implicated in cognitive deficits of neurological and neurodegenerative diseases. There is abundant evidence that the application of ghrelin, an orexigenic hormone regulating appetite and energy balance, abrogates neuroinflammation and rescues associated memory impairment. However, the underlying mechanism is uncertain. In this study, we find that both intraperitoneal (i.p.) and intracerebroventricular (i.c.v.) administration of lipopolysaccharide (LPS) impairs spatial memory in mice. LPS treatment causes neuroinflammation and microglial activation in the hippocampus. Ghsr1a deletion suppresses LPS-induced microglial activation and neuroinflammation, and rescued LPS-induced memory impairment. Our findings thus suggest that GHS-R1a signaling may promote microglial immunoactivation and contribute to LPS-induced neuroinflammation. GHS-R1a may be a new therapeutic target for cognitive dysfunction associated with inflammatory conditions. •GHS-R1a deficiency abrogates spatial learning and memory impairment induced by i.p. administration of LPS.•GHS-R1a deficiency abrogates spatial memory impairment induced by i.c.v. administration of LPS.•GHS-R1a deficiency abrogates LPS-induced impairment in spatial memory retrieval.•GHS-R1a deletion protects again LPS-induced microglial activation in the hippocampus.