Cerebral ischemia/reperfusion (I/R) injury is a leading cause of death and disability globally, particularly in China, and presents significant neurotoxic challenges despite timely revascularization. Polygonatum cyrtonema Hua polysaccharides (PCP) are well-known for their antioxidative, anti-inflammatory and immunomodulatory properties. This study aimed to address an unknown mechanism that regulates oxidative stress and neuroinflammation in cerebral ischemia/reperfusion injury induced by PCP. Our findings demonstrated that cell viability improved significantly when PCP was applied at concentrations of 20, 40 and 80 g/mL for 24 h in Oxygen and Glucose Deprivation/Reperfusion (OGD/R)-stimulated HT22 cells. PCP also markedly decreased Reactive Oxygen Species (ROS) and Malondialdehyde (MDA) levels by over 40% while enhancing Superoxide Dismutase (SOD) activity by approximately 35%. Additionally, PCP significantly reduced pro-inflammatory cytokines production, such as Tumor Necrosis Factor-alpha (TNF-α), Interleukin (IL)-1β and IL-6, by more than 50%. PCP activated the Nuclear factor erythroid 2-related factor 2 (Nrf2) axis and inhibited the Nuclear Factor kappa B (NF-κB) axis in HT22 cells under OGD/R conditions. Essentially, PCP modulates the oxidative stress and inflammation pathways to prevent injury induced by I/R. PCP may therefore be a promising treatment for ischemic stroke.