Background: Sepsis associated encephalopathy (SAE) is a prevalent form of organ dysfunction associated with sepsis. There is no overt central nervous system (CNS) infection accompanying it, yet it carries a significant risk of mortality and can lead to long-lasting neurological complications. The efficacy of Angong Niuhuang Pill (AGNH) in enhancing conditions like cerebral ischemia, cerebral trauma and sepsis has been well-established. Nonetheless, the specific regulatory roles and underlying mechanisms of AGNH in the progression of SAE remain unexplored. Methods: The lipopolysaccharide (LPS) treatment was utilized to construct SAE rat model. Berderson’s neurological examination scoring system was used for scoring. The levels of genes and iron content were examined through enzyme-linked immunosorbent assay (ELISA) or the corresponding commercial kits. The prothrombin time (PT), activated partial thromboplastin time (APTT), thrombin time (TT) and fibrinogen (FIB) level were confirmed through the automatic coagulation analyzer. The number and morphology of neurons were evaluated through hematoxylin eosin (HE) staining. The protein expressions were determined through western blot. Results: The increased Berderson never function score mediated by LPS treatment was attenuated after AGNH or Defetoxamine (DFO, ferroptosis inhibitor) treatment, indicating that AGNH improved neurobehavioral function in juvenile SAE mice. Furthermore, AGNH improved inflammation and coagulation parameters in young SAE mice. AGNH promoted neuronal growth and mitigated neuronal damage in juvenile SAE mice. Additionally, AGNH inhibited ferroptosis and reduced oxidative stress in young SAE mice. Lastly, it was demonstrated that AGNH promoted nuclear factor erythroid 2-related factor 2 (Nrf2)/glutathione peroxidase 4 (GPX4) signaling pathway through up-regulating the Nrf2 and GPX4 protein expressions. Conclusions: This study revealed a novel finding that AGNH has the ability to inhibit GPX4-induced ferroptosis in juvenile SAE mice by modulating the Nrf2/GPX4 signaling pathway. This breakthrough implies that AGNH has promising prospects as a therapeutic agent for SAE.