Introduction: The mechanisms behind Alzheimer’s disease (AD) remain largely unclear. Reactive oxygen species and inflammatory cytokines contribute to inflammation and synaptic dysfunction in AD. This study investigates whether silibinin’s neuroprotective properties act through regulating oxidative stress and inflammation. Methods: Forty-eight Wistar rats (230±20g) were divided into four groups. The control group comprised healthy animals, while the lesion group received amyloid beta (Aβ 1-40 ). The vehicle group received silibinin solvent post-Aβ1-40 injection. Treatment groups received silibinin (50, 100, and 200 mg/kg) after Aβ1-40 injection. Following a passive avoidance behavior test, biochemical analysis of superoxide dismutase (SOD), malondialdehyde, Tumor necrosis factor α (TNF -α) and interleukin-6 (IL-6) was conducted. Results: Administration of 100 mg/kg silibinin significantly reduced serum IL-6 levels compared to the lesion group (P=0.005). All silibinin doses significantly decreased TNF-α levels (P≤0.001). Serum superoxide dismutase (SOD) levels increased significantly in animals treated with 100 and 200 mg/kg silibinin compared to the lesion group (P=0.002, P=0.03). Step-through latency improved in silibinin-treated animals (100 and 200 mg/kg) (P≤0.006). Conclusion: These results suggest silibinin can enhance cognitive function and offer neuroprotection by inhibiting lipid peroxidation and reducing pro-inflammatory cytokines (TNF-α and IL-6) in AD rat models.