Plant extracts have long served as important sources of bioactive compounds, and they are currently the focus of extensive research in the development of novel preventive and therapeutic strategies. However, their health benefits are often limited by low bioavailability. Nanoparticle delivery systems can represent a solution to such limitations. Euphorbia characias is a Mediterranean shrub known to have biological activities, such as inhibiting tyrosinase and showing a potential role as a skin-whitening agent. In this study, an ethanolic extract from E. characias leaves was tested for its inhibitory activity on skin-related enzymes, such as elastase, collagenase, and hyaluronidase, and for sun protection factors. Moreover, the extract was formulated in phospholipid vesicles to improve its local bioavailability and applicability. The vesicles were characterized by size, surface charge, storage stability, and entrapment efficiency. The nanoformulation was also evaluated for antioxidant activity and assayed for cytocompatibility and anti-tyrosinase activity in melanoma cells. Our findings demonstrated that the extract has a photo-protective effect and enzyme-inhibitory properties. E. characias nanoformulation was also cytocompatible and improved the extract’s activity in the cells, suggesting a potential skin application for antimelanogenic treatments and confirming the key role of nanotechnological approaches to maximize plant extract’s potentialities.