Localized tissue renin-angiotensin system (RAS) is an interesting pathway of organ damage. Here, the effect of the brain-penetrating angiotensin converting enzyme (ACE) inhibitor perindopril was studied on lipopolysaccharide (LPS)-induced brain damage, with and without exogenous angiotensin (Ang)-II administration. Animals were divided into 6 groups; a normal control group, an LPS control group (LPS, 3mg/kg, i.p., single dose), two treatment groups receiving perindopril (1 and 2mg/kg/day, i.p.) for 7 days before LPS administration, and two Ang-II/perindopril/LPS groups receiving perindopril and LPS, followed by a single dose of Ang-II solution (5 μl, i.c.v.). Brain tissue Ang-II, Ang-1–7, and NADPH oxidase were estimated using ELISA technique. Nuclear factor kappa-B (NF-κB-p65) was estimated using real time PCR technique, while phosphorylated NF-κB-p65 (p-NF-κB-p65), phosphorylated and non-phosphorylated protein kinase B (p-Akt and Akt) and phosphorylated inhibitor of kappa-B (p-IκBa) were estimated by western blot analysis. Malondialdehyde (MDA), glutathione (GSH), superoxide dismutase (SOD), glutathione-S-transferase (GST), catalase, nitrite and myloperoxidase (MPO) were estimated colorimetrically. Brain tissue inducible and endothelial nitric oxide synthases (iNOS and eNOS) were estimated immunohistochemically, confirmed by a histopathological study. LPS-intoxicated rats showed significantly elevated Ang-II, NADPH oxidase, NF-κB-p65, p-NF-κB-p65, p-IκBa, p-Akt, Akt, p-Akt/Akt ratio, MDA, nitrite, MPO and iNOS levels, coupled with significantly suppressed Ang-1–7, GSH, SOD, GST, catalase, and eNOS levels, which were all corrected by pre-treatment with perindopril in both doses by varying degrees. Exogenous Ang-II significantly ameliorated the protective effects of perindopril. Conclusively, perindopril ameliorates LPS-induced brain damage through modulation of RAS, iNOS/eNOS, p-Akt/Akt and NF-κB signaling pathways.