Several studies have highlighted the health-promoting effects of antioxidants contained in fruit and vegetables. Blueberries are palatable fruits with one of the highest antioxidant contents to be found. Oxidative stress plays a key role in aging and neurodegeneration. In the last 15 years, the effects of blueberries’ polyphenolic compounds in neurons and their influence on brain performance have been explored. Blueberry polyphenols have been shown to enhance neuroprotection through molecular mechanisms involving, beyond a radical scavenging activity, the counteraction of β-amyloid toxicity, neuroinflammation, and excitotoxicity. They normalize sensitivity to neurotransmitters and promote synaptic plasticity, cell growth, and survival and also act by regulation of gene expression. These mechanisms can slow down the process of aging in young animals and reverse age-related decline in aged animals. Cognitive performance in humans is also improved. This represents the basis for new nutraceuticals in the prevention of brain aging and the therapy of neurologic diseases.