Objective To investigate the effects of agmatine on Propofol-induced neurotoxicity in newborn rats. Methods Rats were divided into five groups for follow-up experiments: Control, Propofol, Propofol + 1 mg / kg Agmatine, Propofol + 2. 5 mg / kg Agmatine, and Propofol + 5 mg / kg Agmatine. The number of errors was detected in a platform experiment, while brain moisture content and brain index were determined by a 2, 3, 5-triphenyl tetrazolium chloride method. The Longa method was used to evaluate neural functional defect and postural reflex scores. HE staining was used to detect the degree of pathological damage in the hippocampus. Apoptosis of hippocampal tissue was detected by Nissl staining. Western blot was used to detect protein expression levels of brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), Bax, Bcl-2, Nrf2, p-Nrf2, and heme oxygenase 1 (HO-1). Results Compared with the Control group, the Propofol group exhibited significant increases in the number of platform errors (P<0. 05), brain water content and cerebral index (P<0. 05), neural function defect scores, and posture reflex scores (P< 0. 05), as well as obvious pathological damage. Moreover, the Propofol group exhibited significantly reduced expression of BDNF, NGF, and HO-1 proteins (P<0. 05), p-Nrf2 / Nrf2 ratio (P<0. 05), and numbers of Nissl bodies (P<0. 05), but a significantly higher Bax / Bcl-2 ratio (P<0. 05). Compared with the Propofol group, Propofol+Agmatine groups (2. 5 and 5 mg / kg) exhibited significantly decreased numbers of platform errors ( P< 0. 05), brain water content and cerebral index ( P< 0. 05), neurologic deficit scores (P<0. 05), and posture reflex scores (P<0. 05). Moreover, the degree of pathological damage was significantly improved in Propofol+Agmatine groups, which exhibited significantly increased BDNF and NGF protein expression (P<0. 05), and numbers of Nissl bodies (P<0. 05), and a significantly decreased Bax / Bcl-2 ratio (P<0. 05;. p-Nrf2 / Nrf2 ratio and HO-1 protein expression were also significantly increased ( P<<0.05). Conclusions Agmatine attenuates Propofol-induced neurotoxicity in newborn rats by regulating the Nrf2 / HO-1 signaling pathway.