Aims Perioperative neurocognitive disorders (PND) are associated with cognitive impairment in the preoperative or postoperative period, and neuroinflammation is thought to be the most important mechanisms especially during the postoperative period. The GABAergic system is easily disrupted by neuroinflammation. This study investigated the impact of the GABAergic system on PND after anesthesia and surgery. Methods An animal model of laparotomy with inhalation anesthesia in 16-month-old mice was addressed. Effects of the GABAergic system were assessed using biochemical analysis. Pharmacological blocking of alpha 5GABA(A)Rs or P38 mitogen-activated protein kinase (MAPK) were applied to investigate the effects of the GABAergic system. Results After laparotomy, the hippocampus-dependent memory and long-term potentiation were impaired, the levels of IL-6, IL-1 beta and TNF-alpha up-regulated in the hippocampus, the concentration of GABA decreased, and the protein levels of the surface alpha 5GABA(A)Rs up-regulated. Pharmacological blocking of alpha 5GABA(A)Rs with L655,708 alleviated laparotomy induced cognitive deficits. Further studies found that the P38 MAPK signaling pathway was involved and pharmacological blocking with SB203,580 alleviated memory dysfunctions. Conclusions Anesthesia and surgery caused neuroinflammation in the hippocampus, which consequently disrupted the GABAergic system, increased the expressions of surface alpha 5GABA(A)Rs especially through the P38 MAPK signaling pathway, and eventually led to hippocampus-dependent memory dysfunctions.