Background and Objectives Fractional microneedle radiofrequency systems are popular options to increase elasticity in aging skin. Laser-assisted drug delivery is a promising method for the epidermal injection of topically applied drugs and cosmetic ingredients. This study assesses the safety and efficacy of topical delivery of L-ascorbic acid, vitamin E, and ferulic acid after fractional microneedle radiofrequency treatment for reducing photodamage. Materials and Methods In this prospective, single-center, split-face, controlled pilot study, six women (mean age, 48.0 years; range, 35-57 years; Fitzpatrick skin types III and IV) exhibiting mild to moderate photodamage, underwent a single session of fractional microneedle radiofrequency treatment. The patients were instructed to apply the antioxidant formulation to only one side of the face. Patients were evaluated 3 days, 7 days, and 4 weeks thereafter, using three-dimensional imaging and ultrasound. Ex vivo, the fullthickness human skin was used for molecular and histological evaluation. Statistical analysis was achieved by applying t-tests, MannWhitney U tests, and one-way analyses of variance. Results Compared to the untreated side, the antioxidant-treated side exhibited a significant increase in dermal thickness (10.32% vs. 17.54%, p < 0.05), but not in skin elasticity (4.76% vs. 4.69%, p > 0.05). The difference in erythema between the sides was statistically not significant (p > 0.05). In the ex vivo model, expression of FGF2 in the skin was significantly increased after application of the antioxidant formulation, as compared to results obtained subsequent to fractional microneedle radiofrequency treatment only (p < 0.01). Conclusion This study demonstrates that for the treatment of photodamaged skin, laser-assisted delivery of the antioxidant formulation is a safe and effective adjuvant modality following fractional microneedle radiofrequency.