The skin is the largest human organ and performs essential functions, including water preservation, thermoregulation and protection against solar radiation, trauma and infections. Due to its constant exposure to environmental factors, the skin is subject to natural ageing and various pathologies. Therefore, to maintain its health, homeostasis and delay the signs of ageing, the use of cosmetics and other skin care products is crucial. In particular, the use of natural ingredients derived from plants has been explored for their bioactivity and sustainable framework. For example, grape by-products, such as seeds, pomace and stems, have various biological activities such as UV protection, antioxidant, antimicrobial and anti-inflammatory properties. The use of these by-products has been important as it allows bioactive molecules to be obtained from organic matter which, on a large scale, can cause environmental problems. However, many of these molecules are unstable and susceptible to degradation, which limits their use. In this sense, encapsulation techniques such as liposomes have been explored, as they are capable of increasing stability, bioavailability, solubility and penetration into the skin, among other benefits. In this work, two grape seed extracts were obtained, one from a single grape variety (GSE-Ov) and the other from a mixture of five grape varieties (GSE-Sv). These extracts were analyzed for their antioxidant and antimicrobial activities, as well as their composition and molecular structure. The best extract was obtained from a single wine variety (GSE-Ov) with antioxidant activity, IC50, of 0.079 mg.mL-1 and antimicrobial activity against two strains of Staphylococcus aureus, one sensitive and the other resistant to methicillin, with minimum bactericidal concentrations (MBCs) of 3.13 and 6.25 mg.mL-1, respectively. In addition, no activity was observed against S. epidermidis, a typical microorganism of the normal skin microbiota, which ensures its balance. The main polyphenols identified in GSE-Ov were gallic acid, catechin and procyanidin B1, and FTIR analysis showed that the extraction process was successful, and the extract had a preserved molecular structure and integrity. The most biologically promising extract (GSE-Ov) was encapsulated in pectin-coated soy lecithin liposomes after optimization and characterization, showing an encapsulation efficiency of 88.8% with a polyphenol release of 59.4% in 24 h, a zeta potential of -20.3 mV, an average diameter of 13.6 µm, a uniformity index of 0.637 and a spherical shape. Subsequently, this extract was evaluated for its cytotoxicity, anti-inflammatory activity (production of IL-1α and IL-6) and production of human pro-collagen I α1. Liposomes loaded with GSE-Ov proved to be safe up to concentrations of 5 and 2.5 mg.mL-1 for HaCaT and HDF cells, respectively. In addition, they demonstrated anti-inflammatory activity against IL-1α when tested at 2 mg.mL-1 . This work enabled the valorization of by-products from the wine industry by obtaining a natural extract which showed very promising antimicrobial, antioxidant and anti-inflammatory activities for use in cosmetic formulations.