This study explores the potential of Arbutus unedo L. pomace, a by-product of the food industry, as a natural ingredient for skincare applications. In Portugal, A. unedo L. fruits are traditionally used to produce “Aguardente de Medronho”, a spirit with a protected geographical indication. The distillation process generates pomace, comprising skins, pulp remnants, seeds, and residual alcohol rich in phenolic compounds, whose levels are significantly increased during distillation. In addition to their documented high antioxidant content, these residues also display notable antimicrobial properties. However, their potential benefits for skin health have not yet been explored. The methodology entailed the preparation of the pomace extract and a comprehensive analysis of its polyphenolic content and antioxidant capacity under laboratory conditions and in preclinical cellular models. The by-products demonstrated a high polyphenol content and potent antioxidant activity, comparable to vitamin C. Bioscreening on human skin models (i.e., dermal fibroblasts and keratinocytes) revealed their ability to reduce reactive oxygen species (ROS) formation under oxidative stress in skin cells, highlighting their potential to mitigate skin aging and damage caused by environmental pollutants. Moreover, bioscreens in vitro revealed a high safety profile, without any interference with cell viability at concentrations up to 100 µg/mL. These findings support the use of A. unedo L. pomace extract as a sustainable ingredient for the development of antioxidant-rich and eco-friendly cosmetic or dermatologic products.