Each year, 20 million tons of wine by-products are generated, corresponding to 30% of the total quantity of vinified grapes. Wine by-products are a source of healthy bioactive molecules, such as polyphenols and other molecules (pigments, fibers, minerals, etc.). The abundance of bioactive compounds assures a promising future for nutritional foodstuff production. Wine by-products can be used to fortify aromatized waters and infusions, bread, pasta, dairy products, alcohol, sugary beverages, and processed foods. These innovative products are part of the Mediterranean diet and are of great interest to both human and environmental health. Pre-clinical studies show that consumption of food produced with wine by-products or with their extracts attenuates the inflammatory state and increases antioxidant status. As such, wine by-products provide protective effects against the underlying pathophysiological hallmarks of some chronic diseases such as atherosclerosis, diabetes, hypertension, obesity, and cancer. However, the poor bioavailability warrants further investigation on how to optimize the efficacy of wine by-products, and more clinical trials are also needed. The scientific evidence has validated the uses of the dietary nature of wine by-products and has helped to promote their use as a functional food to prevent chronic human diseases.