In Portugal, grapevine leaves are generally treated as agro-industrial waste, despite being rich in bioactive compounds that offer benefits to human health. This study compiles the most relevant and current data on the phytochemical composition and bioactive properties of grape leaves from both red and white varieties cultivated in the country. These by-products are abundant in flavonoid and non-flavonoid phenolic compounds, such as flavonols, derivatives of hydroxycinnamic acids, carotenoid pigments, and chlorophylls, as well as fatty acids, which have scientifically proven antioxidant, antimicrobial, anti-inflammatory, antidiabetic, cardio-, neuro- and hepatoprotective properties, among others. The combination of these beneficial properties, along with the low toxicity of their compounds, makes grapevine leaves a by-product with great potential for use in the food, pharmaceutical, and cosmetic industries. The key challenge is to develop sustainable methods to reintegrate this by-product into the supply chain, in alignment with the sustainability goals of the 2030 Agenda.