Black raspberry is known to contain a diverse number of phytochemicals, especially polyphenols which have shown health benefits. These compounds might play a role in alleviating β-amyloid (Aβ)-induced neurotoxicity. In this study, we investigated the effect of black raspberry in reducing Aβ toxicity and improving mitochondrial function in the HT-22 cell model. HT-22 cells were co-cultured together with black raspberry extract (BRE) and Aβ and various markers for apoptosis and mitochondrial function were assessed. BRE treatment significantly improved cell viability, reduced reactive oxygen species (ROS) generation, and enhanced mitochondrial biogenesis via upregulation of PGC-1α and Sirt1 expression. Among the isolated fractions, the ethanol fraction (Et-F1) demonstrated the most potent neuroprotective effect. High-performance liquid chromatography identified rutin as a major compound in Et-F1, though it did not account for the full protective effect. In conclusion, our results suggest that BRE might be used as a natural supplementation for combatting Aβ-associated dementia.