Background: The normally acidic pH of stratum corneum (SC) regulates several key protective functions of the skin, including permeability barrier homeostasis and SC integrity and cohesion. Increased pH has been demonstrated in SC of patients with atopic dermatitis (AD), and it was associated impaired barrier function in AD. Objectives: The purpose of this study is to evaluate the efficacy of a moisturizer containing gluconolactone (10%) and glycyrrhetinic acid (2%) in mild-to-moderate AD. Methods: Fifty patients (mean age: 20.5 years, female 58%) with mild-to moderate AD were enrolled in this study. Patients were treated with the moisturizer containing gluconolactone (10%) and glycyrrhetinic acid (2%) twice daily as monotherapy for 4 weeks. Outcome measures included EASI score, investigator global assessment, subject satisfaction, as well as the objective skin evaluation including TEWL, SC pH, and skin hydration. Results: After 4 weeks of therapy, 88% (44/50) of patients completed the clinical trial. There were statistically significant differences between baseline and 4 weeks after applying the moisturizer in terms of EASI score, TEWL, SC pH, and skin hydration (p < .05). Conclusion: The moisturizer containing gluconolactone (10%) and glycyrrhetinic acid (2%) was effective in ameliorating AD severity, and shown to recover acidic SC pH, TEWL, and skin hydration.