Objective: Stroke is a leading cause of disability, often resulting from interrupted blood flow in the brain. Several mechanisms, such as inflammatory pathways, have been reported to play a role. Niclosamide, an oral drug for tapeworm infections, has shown potential effects in cancer, infections, and pain relief. This study examines niclosamide’s neuroprotective effects in a rat model of ischemic stroke induced by bilateral common carotid artery (BCA) occlusion. Methods: Acute effects of niclosamide (5, 10, and 25 mg/kg doses in DMSO) were evaluated in a BCA occlusion stroke model. Behavioral deficits and recovery were assessed using grid walking, modified neurological severity score (mNSS), and open field tests. Hippocampal histology was examined with H&E and Nissl staining. Key molecular markers, including cAMP, TNF-α, nitric oxide synthase (NOS), beclin-1, and the AMPK pathway, were analyzed. Results: Niclosamide at 10 mg/kg significantly reduced neurological deficits, necrotic degeneration, hemorrhage, and inflammatory cells (P < 0.01). TNF-α levels and inflammation decreased (P < 0.05), with reduced AMPK activation and beclin-1, suggesting decreased autophagy (P < 0.01). Additionally, niclosamide lowered brain edema by reducing NOS levels (P < 0.05) and increased cAMP, contributing to neuroprotection. Interpretation: Findings suggest that 10 mg/kg niclosamide treatment improves neurological outcomes post-stroke via multiple molecular pathways, demonstrating its potential for neuroprotection.