BackgroundThe most visible sign of facial aging is often seen in the periocular area. However, periocular rejuvenation remains challenging due to the particularity of periocular anatomic locations.AimsWe aimed to evaluate the efficacy and safety of the fractional‐ablative CO2 laser‐facilitated recombinant human collagen permeation in periocular rejuvenation.Patients/MethodsThis 3‐month prospective single‐blinded and self‐controlled trial enrolled 26 patients with periocular aging who underwent the treatments of fractional‐ablative CO2 laser along with laser‐facilitated recombinant human collagen permeation. Following the treatments, the patients were quantitatively assessed by various periocular skin aging indices before and after the treatment and monitored for any related adverse events.ResultsThe patients showed significant improvements with the periocular skin aging indices 3 months after the treatments, which were detailed with a 47.3% decrease in lower eyelid skin rhytids, a 41.4% decrease in the lower eyelid skin texture, a 35.0% decrease in the static crow's feet, a 29.3% decrease in the amount of upper eyelid laxity, and a 20.2% increase in the MRD1 as compared with baseline (p < 0.05). Moreover, total skin thickness under ultrasound was increased in both upper and lower eyelids (5.6% and 3.3%, p < 0.05, respectively). Moreover, six patients (23.1%, 6/26) had erythema for 2 weeks, and two (2/26, 7.7%) had mild hyperpigmentation for 3 months.ConclusionsFractional‐ablative CO2 laser combined with laser‐facilitated recombinant human collagen permeation can be a safe and effective treatment for periocular rejuvenation.