Background: Periorificial dermatitis (POD) is a common inflammatory skin condition primarily affecting infants, children, and young women. Novel therapies such as phosphodiesterase 4 (PDE4) inhibitors provide promising non-steroidal anti-inflammatory treatment options. Objective: This study evaluated the efficacy and safety of topical crisaborole 2% ointment, a PDE4 inhibitor, for treating pediatric patients with POD. Methods: A randomized, double-blind, vehicle-controlled trial included 23 participants aged 3 months to 18 years. Patients were treated with crisaborole 2% ointment or placebo for 4 weeks, followed by a 4-week treatment-free observational period. Primary endpoints were a 50% reduction in the Perioral Dermatitis Severity Index (PODSI) and an Investigator’s Global Assessment (IGA) score of 0 or 1 by day 14. Assessments were also conducted on days 29 and 58. Secondary measures included changes in Quality-of-Life Index scores over time and safety evaluations. Results: Both groups demonstrated improvement in PODSI and IGA scores during treatment.Although a small, non-significant numerical trend favored the crisaborole group across primary and secondary endpoints, no statistically significant differences between crisaborole and placebo were observed at any time point. Mild burning or stinging were reported more frequently in the crisaborole group, but they were generally tolerable. Conclusion While there was a modest numerical trend favoring crisaborole, its efficacy was not statistically superior to placebo in this small pilot study. Larger studies are needed to further validate the efficacy of crisaborole for the treatment for POD.