Alzheimer’s disease is associated with amyloid-β plaques eliciting neuronal oxidative stress. Many naturally occurring compounds have antioxidant properties, but it is unclear if this alone protects against amyloid-β exposure. This study investigated the protective effects of selected bioactive compounds against amyloid-β and pro-oxidant-evoked neurotoxicity in PC12 cells. Neither resveratrol, (−)-epigallocatechin-3-gallate, cyanidin rutinoside or grape skin extract protected PC12 cells against H 2 O 2 or tert butyl hydroperoxide toxicity. Amyloid-β resulted in a concentration-dependent reduction in PC12 cell viability that was unaffected by resveratrol or cyanidin rutinoside pre-treatment. By contrast, (−)-epigallocatechin-3-gallate and grape skin extract significantly reduced amyloid-β-evoked neurotoxicity (by 40%). Only (−)-epigallocatechin-3-gallate was directly able to inhibit amyloid-β aggregate and fibril formation. These results suggest that (−)-epigallocatechin-3-gallate protects neuronal cells by disrupting amyloid-β fibril formation; bioactive polyphenols which disrupt fibril aggregation may confer additional neuroprotection when compared against antioxidant activity alone.