Background: Genitourinary syndrome of menopause (GSM) is a chronic, progressive consequence of hypoestrogenism that affects vaginal, sexual and lower urinary tract health. Treatments include local vaginal estrogen, intravaginal prasterone, oral ospemifene, hyaluronic acid preparations, moisturizers and lubricants and energy-based interventions, but direct head-to-head randomized evidence is limited. Objective: To compare the relative efficacy and safety of contemporary GSM therapies using a systematic review and class-level network meta-analysis of randomized controlled trials. Methodology: MEDLINE/PubMed, Scopus, Cochrane CENTRAL, Web of Science, Google Scholar, ClinicalTrials.gov and WHO ICTRP were searched from inception to 1 March 2026, with backward and forward citation searching. Randomized controlled trials enrolling postmenopausal women with GSM, vulvovaginal atrophy or atrophic vaginitis were eligible. Interventions included local vaginal estrogen, prasterone, ospemifene, hyaluronic acid, moisturizers/lubricants, carbon dioxide laser and radiofrequency. Two reviewers independently screened records and extracted data. The primary efficacy outcome was change in the most bothersome symptom or, when unavailable, dyspareunia or vaginal dryness measured closest to 12 weeks. Risk of bias was assessed with RoB 2. Direct and indirect evidence were synthesized using a random-effects class-level network approach. Results: Twenty-six randomized trials were included. The evidence network was anchored primarily by placebo/sham and local estrogen. In the harmonized continuous symptom network, local estrogen (standardized mean difference [SMD] 0.89, 95% confidence interval [CI] 0.29 to 1.48) and hyaluronic acid (SMD 0.84, 95% CI 0.01 to 1.68) were superior to placebo/sham, while radiofrequency showed a large but sparse estimate (SMD 1.29, 95% CI 0.21 to 2.38). Confidence intervals crossed the null for carbon dioxide laser, moisturizer, ospemifene and prasterone. In the smaller binary responder network, both local estrogen (risk ratio [RR] 2.39, 95% CI 1.69 to 3.38) and hyaluronic acid (RR 2.32, 95% CI 1.64 to 3.29) improved response rates versus placebo/sham. Across the broader evidence base, local estrogen showed the most consistent improvement in vaginal pH and epithelial maturation; prasterone and ospemifene remained effective alternatives in dedicated placebo-controlled programs. Safety events were generally mild and infrequent, but device estimates were less stable and sparse device-related loops showed local inconsistency. Conclusions: Local vaginal estrogen remains the benchmark therapy for GSM. Prasterone and ospemifene are evidence-based alternatives, hyaluronic acid is the strongest active non-hormonal option and moisturizers/lubricants remain appropriate for symptom-focused first-line care. Carbon dioxide laser and radiofrequency should be interpreted cautiously until stronger sham-controlled and long-term data are available.