Objective To investigate the effect of granulocyte colony-stimulating factor (G-CSF) on cognitive impairment in Alzheimer’s disease(AD) in rats and its effect on brain inflammatory response. Methods Forty-five male Sprague-Dawley rats were randomly divided into 3 groups: sham operation group, model group, and G-CSF group. Rat models were induced by intracerebro ventricular injection of amyloid beta-peptides 1-42 (Aβ_1-42), and then G-CSF were given to G-CSF group. The learning and memory function and brain histopathological changes were observed and compared. The expression of nuclear factor κB p65 (NF-κB p65), phosphorylated p38 mitogen activated protein kinase (p-p38MAPK), inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), tumor necrosis factor α(TNF-α) and interleukin-1β(IL-1β) were detected by Western blotting. The levels of iNOS, COX-2, TNF-α and IL-1β mRNA were detected by Real-time PCR. Results The number of neurons in the model group decreased significantly, the nuclear condensation was obvious and the nucleolus was unclear. Neuronal nuclear condensation was significantly improved in G-CSF group. The escape latency of the sham group, model group and G-CSF group were (35.68±6.73) s, (57.92±7.35) s and (40.27±8.91)s. The swimming time of the target quadrant was 54.72%±4.22%, 36.73%±3.2% and 44.68%±4.01%. The times of crossing the platform were 8.7±2.1, 3.9±1.6 and 6.5±1.7. Compared with the model group and the control group, the escape latency of G-CSF group were significantly shorter, target quadrant swimming time increased significantly, through the platform number increased significantly, the difference had statistical significance (P<0.05).In the sham group, model group and G-CSF group, the protein levels of NF-κB p65 were 0.144±0.033, 0.502±0.035 and 0.473±0.061, the protein levels of p-p38MAPK were 0.194±0.021, 0.511±0.039 and 0.266±0.048. Compared with the model group, the levels of F-κB p65 and p-p38MAPK protein in the sham group and G-CSF group decreased significantly, and the difference was statistically significant(P<0.05). Compared with the model group, the protein and mRNA levels of iNOS, COX-2, TNF-α and IL-1β in the sham group and G-CSF group were significantly lower than those in the model group (P<0.05).Conclusion G-CSF can improve the learning and memory dysfunction of rats with Alzheimer’s disease probably through inhibiting the activation of p38 MAPK and NF-κB p65 signaling pathways and down-regulating iNOS, COX-2, TNF-α and IL-1β expressions to inhibit the neuroinflammatory state of the brain.