Background and Objectives: Genitourinary syndrome, previously defined as vulvovaginal atrophy, manifests with signs and symptoms deriving from estrogen diminution in the female genitourinary tract. Stable ozonides are derivatives of artemisinin found to be stable against strong basic and acidic conditions. Vitamin E is an important antioxidant diminishing the output of reactive oxygen species in the oxidation of fats and the emanation of free radicals, reducing cellular injury and aging. The primary aim of the present study was to assess the positive effects of an ozonide plus a vitamin E acetate-based compound (Ozoile) on genitourinary syndrome symptom relief after a maximum of 20 days of treatment. Materials and Methods: The inclusion criteria for patients' enrollment were women of child-bearing age or in menopause reporting genitourinary syndrome's related symptoms, such as pain, burning, a bad smell, dyspareunia, dryness, itching, bleeding, and nervousness. The exclusion criteria were Sjogren's syndrome and patients administered retinoic acid, an agent that causes mucosal dryness. Participants completed a questionnaire before and after 20 days of treatment. Results: The incidence of pain decreased from 16.7% to 11.8% (p-value < 0.0001). In addition, the mean symptom intensity decreased from 2.10 to 0.87 (p-value < 0.0001). Dryness was the most frequent pre-treatment symptom and decreased from 85.5% to 53.8% (p-value < 0.0001) (mean: 2.21 vs. 0.90; p-value < 0.0001). Conclusions: Ozoile was effective in reducing most gynecologic symptoms related to genitourinary syndrome. However, further studies are needed to compare its effect with other standards of care.