Several animal studies demonstrated that the volatile anesthetic isoflurane could influence the blood-brain barrier (BBB) integrity, which involved the cognitive impairment. Increasing evidence has also shown that the receptor for advanced glycation end-products (RAGE) played a major role in maintaining the integrity of BBB. The present study aimed to determine whether the RAGE-specific antibody protects against BBB disruption and cognitive impairment induced by isoflurane exposure in aged rats. 108 aged rats were randomly divided into four groups: (1) control group (Control); (2) 4 h of 2% isoflurane exposure group (ISO); (3) RAGE antibody (20 μL, 2.5 μg/μL) treated + 4 h of 2% isoflurane exposure group (anti-RAGE+ISO); (4) RAGE antibody (20 μL, 2.5 μg/μL) treated group (anti-RAGE). The isoflurane anesthesia resulted in the upregulation of hippocampal RAGE expression, disruption of BBB integrity, neuroinflammation, and beta-amyloid (Aβ) accumulation in aged rats. In addition, significant cognitive deficits in the Morris water maze test was also observed. The antibody pretreatment resulted in significant improvements in BBB integrity. Furthermore, the expression of RAGE and proinflammatory mediators, as well as, Aβ accumulation were attenuated. Moreover, the antibody administration attenuated the isoflurane-induced cognitive impairment in aged rats. These results demonstrate that RAGE signaling is involved in BBB damage after isoflurane exposure. Thus, the RAGE antibody represents a novel therapeutic intervention to prevent isoflurane-induced cognitive impairment.