Photoaging is a multifactorial process characterized by progressive degradation of dermal collagen, reduced skin elasticity, textural irregularities, and uneven skin tone. Dihydromyricetin (DHM), a naturally occurring flavonoid, possesses antioxidant and anti-inflammatory properties that may be beneficial for skin rejuvenation. However, clinical data on the topical application of DHM in humans remain limited. To evaluate the efficacy and safety of a topical dihydromyricetin-containing serum for facial and neck rejuvenation in individuals with photoaged skin. This prospective, single-arm clinical study enrolled 30 participants aged 30–45 years with Fitzpatrick skin types III–V and moderate to severe photoaging. Participants applied a DHM-containing serum to the face and neck twice daily for 8 weeks, followed by a 4-week post-treatment observation period. Clinical assessments were performed at baseline and at weeks 4, 8, and 12 using objective bioengineering instruments, including Cutometer ® for skin elasticity, Colorimeter ® for skin radiance (individual typology angle, ITA), Antera 3D ® for skin texture, pore characteristics, and redness; and VISIA ® UV spots. Safety and tolerability were also monitored throughout the study. Significant improvements in skin elasticity parameters (R0, R3, and R8) over the face and neck were observed at week 8 and were maintained at week 12 (all p < 0.05). Skin radiance, as measured by ITA, showed a significant increase at week 8 with sustained improvement during follow-up. Antera 3D ® analysis demonstrated significant reductions in infraorbital skin roughness, pore area, and redness. No serious adverse events were reported. Mild, transient dryness or irritation was noted in a small number of participants and resolved without intervention. The topical application of a dihydromyricetin-containing serum was safe and associated with clinically meaningful improvements in skin elasticity, texture, and radiance in photoaged facial and neck skin. These findings support the potential role of DHM as a topical antioxidant for cosmetic skin rejuvenation, particularly in Asian skin types.