Abstract Background Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that accounts for most dementia cases. It has become a serious international health and economic concern as there is no effective treatment. Naturally derived products, particularly polyphenols (PP), have become very popular for developing effective therapeutic strategies for AD. PP apply their neuroprotective actions through targeting various pathological hallmarks of the disease, such as Aβ and/or aggregation, oxidative stress and mitochondrial dysfunction. Aβ aggregation is majorly implicated in the pathogenesis of AD. Therefore, finding a way to attenuate Aβ‐induced toxicity could be a potential approach for disease‐modifying treatments of AD. In the current study, the effect of polyphenolic extract from different sorghum varieties was assessed against Aβ 42 ‐induced cytotoxicity. Method A cell viability assay (MTS) was utilized to assess the protective effect of the extracts on Aβ‐induced cytotoxicity in human neuroblastoma BE (2)‐M17 cells. Following that, a thioflavin T (Th‐T) assay was performed to assess the anti‐Aβ aggregation effect of the extracts. Result The sorghum extracts significantly increased the cell viability. Of the six different tested extracts, QL33(2000 µg/ml) and B923296(1000 µg/ml) demonstrated the strongest and weakest protective effect in decreasing Aβ‐induced cell death (p < 0.01), respectively. In addition, the sorghum extracts were effective at inhibiting the Aβ aggregation. Conclusion Sorghum polyphenolic extracts demonstrated a promising neuroprotective effect against Aβ‐induced cytotoxicity and therefore can be considered as a potential naturally derived agent for AD treatment. However, further studies are required to confirm the anti‐AD effects of these sorghum extracts.