Abstract This study evaluated the possible neuroprotective effect of Allium atroviolaceum extract (AaE)-synthesized selenium nanoparticles (SeNPs) on aluminum (Al)-induced neurotoxicity in mice, explaining the likely mechanisms. Mice were divided into five groups: G1, control; G2, AaE group that received AaE (200 mg/kg) for 4 weeks; and groups 3, 4, and 5 received AlCl₃ (100 mg/kg) for 3 weeks. After that, G4 received AaE (200 mg/kg), and G5 received SeNPs-AaE (0.5 mg/kg) for another 1 week. Exposure to AlCl₃ boosted oxidative damage in brain tissue as evidenced by a reduction in glutathione concentrations and other antioxidant enzymes along with increased lipid peroxidation and nitric oxide levels. There was also a rise in the concentrations of interleukin-1β, TNF-α, and cyclooxygenase-II activities. AlCl₃-treated mice showed reduced brain-derived neurotrophic factor (BDNF) and dopamine levels, increased acetylcholinesterase (AChE) activity, and reduced Bcl-2, and Bax, and caspase-3 activities. Treatment with SeNPs-AaE significantly reduced markers of oxidative stress, inflammation, and apoptosis. In addition, in SeNPs-AaE-treated rats, levels of BDNF and dopamine were significantly increased along with a reduction in AChE as compared with the AlCl₃ group. Therefore, our results indicate that SeNPs-AaE has a potential neuroprotective effect against Al-mediated neurotoxic effects because of its powerful antioxidant, anti-inflammatory, anti-apoptotic, and neuromodulatory activities.