Given the anti-inflammatory properties of Resveratrol, this paper proposes developing a grape seed oil-in-water microemulsion (ME) for topical administration to treat inflammatory skin pathological conditions. Thermal analyses confirmed compatibility between Resveratrol, grape seed oil, Tween 80, and Span 80 used in the formulations. Two compositions (ME1 and ME2) were selected from a pseudo-ternary diagram prepared by components titration. ME1 (50% water, 35% surfactant, 15% oil) and ME2 (60% water, 30% surfactant, 10% oil) showed mean droplet sizes of 23.1 ± 0.7 nm and 24.9 ± 1.7 nm (PdI = 0.34 and 0.47), zeta potential between -11.7 ± 0.5 and -13.6 ± 0.9 mV, and pH values of 6.2 ± 0.5 and 7.1 ± 1.1, respectively. Rheological analyses revealed Newtonian behavior and low viscosity, with physical stability for 60 days at room temperature. In vitro drug permeation studies using porcine skin demonstrated that ME increased Resveratrol penetration into deeper skin layers by fourfold (p < 0.001) compared to the control solution (ME1: 2.9 ± 0.1 μg/cm, ME2: 2.4 ± 0.1 μg/cm), while reducing retention in the stratum corneum. HET-CAM experiments indicated safety for topical application. In conclusion, the ME was a promising alternative for future clinical investigations to treat inflammatory skin conditions.