Ferroptosis is an iron-dependent and membrane lipid peroxidation-mediated form of programmed or regulated cell death. A number of recent studies have demonstrated that ferroptosis contributes to Alzheimer's disease (AD)-mediated nerve cell death. Melatonin demonstrates strong antioxidant properties and offers protective benefits for the brain in the context of AD. However, it is not fully known whether melatonin protects against ferroptosis and whether ferroptosis affects amyloid precursor protein (APP) processing. In this study, we studied the effects of melatonin on SH-SY5Y cells-induced ferroptosis using erastin, and ferrostatin-1 was used as a ferroptosis inhibitor. To confirm the occurrence of ferroptosis, we conducted measurements of cell cytotoxicity, intracellular iron, reactive oxygen species (ROS), and 4-hydroxynonenal (4-HNE). The protein expressions that were regulated by either ferroptosis or APP processing were measured. Our results revealed that erastin increased intracellular iron levels, ROS, and 4-HNE lipid peroxidation in SH-SY5Y cells, resulting in an increased percentage of cell death. Erastin disrupted the regulation of proteins involved in ferroptosis and increased the production of amyloid beta (Aβ) through APP proteolysis. Following melatonin treatment, intracellular iron, ROS, and 4-HNE levels were significantly reduced. Additionally, the cystine/glutamate antiporter (system xc) and glutathione peroxidase 4 (GPX4) were increased, and acyl-CoA synthetase long chain family member 4 (ACSL4) was diminished. APP, β-site-APP cleaving enzyme 1 (BACE1), presenilin 1 (PS1) and Aβ production were alleviated in erastin-treated SH-SY5Y cells. In conclusion, melatonin effectively inhibits ferroptosis-related cell death and AD-like conditions induced by erastin in SH-SY5Y human neuroblastoma cell lines.