Background: Aluminum chloride (AlCl3) is a known potent environmental neurotoxin causing progressive neurodegenerative changes in the brain. The herb Pluchea lanceolata is commonly known as “Rasana” and used as a nerve tonic in neuroinflammatory conditions in Indian system of medicine. Objective: To evaluate the neuroprotective activity of hydroalcoholic extract of P. lanceolata in chronic AlCl3-induced neurotoxicity in Swiss albino mice. Materials and Methods: Albino mice were categorized into four different groups; Group 1served as vehicle control, Group 2 mice were administered with AlCl3, 40 mg/kg body weight by intraperitoneal route for 45 consecutive days. Groups 3 and 4 mice were administered with AlCl3, 40 mg/kg body weight intraperitoneal for 45 consecutive days along with hydroalcoholic extract of P. lanceolata at 200 and 400 mg/kg body weight. Results: Chronic administration of AlCl3resulted in behavioral deficits, triggered lipid peroxidation, increased acetylcholinesterase (AChE) activity, and histological alterations. Co-administration of hydroalcoholic extract of P. lanceolata attenuated many of the AlCl3-induced alterations such as behavioral, lipid peroxidation, AChE, and histological changes of brain tissue. Conclusion: The results of the present study have demonstrated the protective role of hydroalcoholic extract of P. lanceolata against AlCl3-induced neurotoxicity in Swiss albino mice. The neuroprotective efficacy of P. lanceolata can help reduce the symptoms caused by toxic protein aggregates in several degenerative diseases.