Blackberry ingestion has been demonstrated to attenuate brain degenerative processes in rodents with the benefits ascribed to the (poly)phenolic components. The aim of this work was to assess the efficacy of blackberry polyphenolics in a neurodegeneration cell model before and after simulated gastrointestinal digestion. Digested blackberry metabolites protected neuroblastoma cells from H₂O₂-induced death at low, non-toxic levels that approach physiologically-relevant serum concentrations. However, the original extracts were not protective even at fivefold higher concentrations. This potentiation may reflect alterations in the polyphenolic composition caused by the digestion procedure, as detected by liquid-chromatography-mass spectrometric analysis. This protection was not caused by modulation of the intracellular antioxidant capacity or through alteration of glutathione levels, although the original extract influenced both of these parameters. This work reinforces the importance of evaluating digested metabolites in disease cell models and highlights the possible involvement of other mechanisms beyond antioxidant systems.