Plant-derived polyphenols have attracted the attention of scientists, the public, and the media due to their potential use as nutraceutical products. The high quantities of polyphenols found in some berry species, e.g. Vaccinium species such as blueberries and lingonberries, and their reported antioxidant and anti-inflammatory properties, could be beneficial for brain aging and neurodegenerative disorders. The neuroprotective potential of various polyphenolic compounds have been validated using a variety of in vivo and in vitro techniques. Both in vivo and in vitro methodologies have their respective advantages and disadvantages, including, but not limited to, cost, time, use of resources and technical limitations. For example, in vivo studies can better evaluate the effects of protective compounds and/or their metabolites on various tissues, including the brain, whereas in vitro studies can better discern the cellular and/or mechanistic effects of compounds. This short review is meant to provide a synopsis of some of the inherent benefits and drawbacks of methods used for assessing neuroprotection and how findings may translate to the human population, particularly related to my specific area of research analyzing the potential neuroprotective effects of berries and their associated polyphenolic compounds.