Accumulation of aluminium (Al) in the brain is known to be a toxic insult that result in neurodegenerative diseases and melatonin is known to have neuroprotective role. The present study was designed to investigate the neuroprotective effects of melatonin for aluminium chloride (AlCl3)-induced neurotoxicity in rats. Twelve-week old male Wistar rats were orally received 175 mg/kg AlCl3 with or without 5 mg/kg melatonin intraperitoneal pretreatment. Group 3 intraperitoneally recieved 5 mg/kg melatonin and group 4 rats were orally treated with saline solution for 8 weeks. A series of behavioral tests, biochemical analysis and expression of AD-associated proteins in the brain were determined after 7 weeks of all treatments. Our results indicated that AlCl3 treatment tends to induce memory and cognitive impairment. However, melatonin treatment attenuated amyloid beta (A?) (1–42) level by decreasing ?-secretase, augmented low-density lipoprotein receptor-related protein 1, and neprilysin protein expression. Moreover, AlCl3 -induced endoplasmic reticulum (ER) stress and oxidative stress was attenuated by melatonin supplementation. In conclusion, these findings demonstrate a protective role of melatonin against A? peptide accumulation, ER stress and oxidative stress in the AlCl3 -treated AD model. Hence, the melatonin supplement might be an alternative way to alleviate the development of AD. © 2020 Elsevier Ltd