Long duration of anesthesia may induce toxicity in the developing brain. However, little is known about the effects of the combination of surgery and anesthesia on the developing brain. The mechanisms for the effects are not clear. To determine these effects, postnatal day 7 male and female Sprague-Dawley rats were exposed to 3% sevoflurane for 2 h with or without right common carotid exposure. Pyrrolidine dithiocarbamate (PDTC), an anti-inflammatory agent, was given 30 min before and 6 h after the carotid exposure. Anti-glial cell-derived neurotrophic factor (GDNF) antibody or GDNF was given at the end of sevoflurane exposure. We found that anesthesia-surgery induced learning and memory impairment assessed by Barnes maze and fear conditioning. Anesthesia-surgery also induced neuroinflammation and reduced the level of glial cell-derived neurotrophic factor (GDNF, 10.6 +/- 0.6 pg/mg protein of control rats vs. 7.7 +/- 0.4 pg/mg protein of anesthesia-surgery rats, n = 17, p = 0.007) and neurogenesis in the hippocampus. PDTC inhibited these surgical effects (GDNF level 9.7 +/- 0.6 pg/mg protein of anesthesia-surgery plus PDTC rats, n = 17, p = 0.763 vs. control rats). Intracerebroventricular injection of an anti-GDNF antibody but not its heat-inactivated form induced learning and memory impairment in control rats. Intracerebroventricular injection of GDNF attenuated learning and memory impairment after anesthesia-surgery. We conclude that anesthesia-surgery in neonatal rats induces neuroinflammation, which then leads to a decreased level of GDNF and neurogenesis in the hippocampus and cognitive impairment. GDNF decrease plays an important role in anesthesia-surgery-induced cognitive impairment.