Walnuts are commonly found in our diet and have been recognized for their nutritious properties for a long time. Traditionally, walnuts have been known for their lipid profile which has been linked to a wide array of biological properties and health-promoting effects. In addition to essential fatty acids, walnuts contain a variety of other bioactive compounds such as, vitamin E and polyphenols. Among common foods and beverages, walnuts represent one of the most important sources of polyphenols, hence, their effect over human health warrants attention. The main polyphenol in walnuts is pedunculagin, an ellagitannin. After consumption, ellagitannins are hydrolyzed to release ellagic acid, which is converted by gut microflora to urolithin A and other derivatives, such as urolithins B, C and D. Ellagitannins possess well known antioxidant and anti-inflammatory bioactivity and several studies have assessed the potential role of ETs against disease initiation and progression, including cancer, cardiovascular and neurodegenerative diseases. The purpose of this review is to summarize current available information relating to the potential effect of walnut polyphenols in health maintenance and disease prevention.