Alzheimer?s disease (AD) is the most common dementia causing progressive loss of memory and compromised cognitive functions. Although the neurotoxic mechanisms underlying AD have yet to be fully elucidated, hyperglycemia seems to trigger oxidative and inflammatory responses in the brain of afflicted patients. Removal of free radicals reduces the neurotoxic effects of hyperglycemia in AD models. In this study we investigated the neuroprotective effects of the antioxidant phytoconstituents oleuropein (OLE), rutin (RUT), luteolin (LUT) and Sallylcysteine (SAC) in an experimental model combining the exposure to high glucose (HG, mimicking chronic hyperglycemia) plus amyloid-? peptide 1?42 (A?1-42, mimicking AD) in primary hippocampal neurons. Cells were pre-treated with OLE, RUT, LUT or SAC (10?1000 nM), and then co-treated with high glucose (GLU, 150 mM) for 24 h plus 500 nM oligomeric A?1-42 for 24 h more. Cell viability and reactive oxygen species (ROS) formation were assessed as indices of survival/toxicity and oxidative stress, respectively. Activity/expression of antioxidant enzymes, toxic adducts, inflammatory molecules, mitochondrial membrane potential (??m) and the pattern of amyloid aggregation were also assessed. The GLU + A?1-42 treatment significantly decreased cell viability, increased ROS formation, reduced superoxide dismutase, catalase, glutathione peroxidase and glutathione reductase activities, augmented Advanced Glycation End Products- and 4-hydroxynonenal-adducts generation, increased 3-nitrotyrosine and inflammatory outcomes such as inducible nitric oxide synthase, interleukin 1? and Tumor Necrosis Factor ?, decreased MMP and augmented amyloid aggregation. All phytoconstituents reduced in a differential manner all toxic endpoints, with SAC showing the highest efficacy in preventing loss of cell viability and oxidative damage, whereas RUT was most efficacious in mitigating inflammatory endpoints. Combined, the results of this study suggest that protection afforded by these compounds against GLU + A?1-42-induced cell damage in hippocampal neurons is attributable to their properties as redox modulators, which might act through a concerted mechanism oriented to reduce oxidative stress and neuroinflammation.