Brunfelsia grandiflora is a South American solanaceae widely used since long ago for its recognized medicinal properties. We have recently reported its chemical composition, showing a relevant number of bioactive compounds with antioxidant capacity, and proved the cytoprotective and antioxidative stress potential of B. grandiflora in cultured endothelial cells. Since B. grandiflora extracts have shown effects on the central nervous system, the present study was designed to show the potential cytoprotective capacity and the antioxidative stress potential of phenolic extracts from the plant on cultured neuron-like cells, as a model to reduce the presentation or effects of chronic diseases of the nervous system. To this end, we studied its reactive oxygen species (ROS)-reducing capacity, its antioxidant defense mechanisms, and some molecular markers involved in redox balance and apoptosis. The results show that cell survival and most changes in biomarkers related to oxidative status, ROS, reduced glutathione, glutathione peroxidase and reductase, malondialdehyde, and caspase 3/7 activity, and molecular expression of cell death-related genes (BAX, BNIP3, and APAF1), NFκB, SOD, and NRF2 (genes from oxidative stress—antioxidants) induced by oxidative stress were prevented by either co- or pretreatment of neuron-like cells with B. grandiflora extracts (25–200 µg/mL). The results demonstrate the chemoprotective potential of the plant and support its medicinal use.