Alzheimer's disease (AD) is one of the most common neurodegenerative disorders in recent world, characterized by increased production of amyloid beta in the nervous system with an ultimate effect of apoptotic neurodegeneration. This study was aimed to investigate the neuroprotective effect of black soybean anthocyanins in a neurodegenerative model of amyloid beta 1–42 (Aβ1–42). Aβ1–42 was treated to HT22 cell lines or adult male rats via intra-cerebro-ventricular injection to induce neurotoxicity in these experimental models. Anthocyanins were treated 0.2 mg/kg in case of cell lines or 4 mg/kg intragastrically to adult rats to protect against Aβ-induced neurodegeneration. Assay for cell viability, mitochondrial membrane potential (Ψm), intracellular free Ca2+ and apoptotic cells (fluoro-jade B and TUNEL) were performed in vitro while western blot analyses were performed to the hippocampal proteins of adult rats. Our results showed that Aβ1–42 treatment reduced cell viability, disturbed the Ψm and Ca2+ homeostasis in and out of the cell, and increased neuronal apoptosis. Treatment with anthocyanins for 12 hr retained the cell viability, normalized Ψm and Ca2+ level, and decreased the neuronal cell death. In accordance, anthocyanins reversed Aβ-induced effect on protein expression of mitochondrial apoptotic pathway (Bax, cytochrome C, caspase-9 and caspase-3) and major Alzheimer's markers i.e. Aβ, APP, P-tau and BACE-1. Overall, our results showed that anthocyanins are potential candidates to treat neurodegenerative disorders like AD.