ObjectiveThis pooled analysis aims to demonstrate the clinical efficacy and safety of combined desmopressin and anticholinergic therapy in the treatment of pediatric nocturnal enuresis (NE).MethodsA systematic search was conducted through PubMed, MEDLINE, EMBASE, ResearchGate, and Cochrane Library to identify all randomized controlled trials (RCTs) comparing monotherapy with desmopressin versus combined therapy with desmopressin and anticholinergic agents for the treatment of NE. Data analysis was performed using RevMan version 5.4.1.ResultsThis study included 8 RCTs involving a total of 659 patients. The frequencies of complete response (CR), partial response (PR), and nonresponse (NR) were computed for both short‐term treatment (1 month) and long‐term treatment (3 months). Additionally, alterations in the mean number of NE episodes, adverse events, and relapse were assessed. Our analysis indicates that, in comparison to the monotherapy group, the combination therapy group plays a pivotal role in augmenting the CR odds and diminishing the NR ratios in both short‐term and long‐term treatments (1 month CR ratio [risk ratio (RR): 1.84; 95% confidence interval (CI): 1.22–2.76; p = 0.003, I2 = 72%]; 3 months CR ratio [RR: 1.48; 95% CI: 1.25–1.76; p < 0.00001, I2 = 0%]; 1 month NR ratio [RR: 0.67; 95% CI: 0.55–0.82; p = 0.0001, I2 = 0%]; 3 months CR ratio [RR: 0.37; 95% CI: 0.19–0.73; p = 0.004, I2 = 0%]). Furthermore, in both short‐term and long‐term treatment, the combined therapy group exhibits a greater magnitude of change in the average number of NE episodes compared to patients receiving monotherapy (1 month, mean difference [MD] = −2.97; 95% CI: −4.23 to −1.71, p < 0.0001; 3 months, MD = −4.30; 95% CI: −7.18 to −1.43, p = 0.003). Moreover, the combination therapy group exhibits a significant reduction in the recurrence rate (RR: 0.36; 95% CI: 0.15–0.86; p = 0.02). There is no significant difference in the incidence of adverse events between the two groups (RR: 1.16; 95% CI: 0.58‐2.31; p = 0.67).ConclusionCombining desmopressin with anticholinergic medications is more effective for NE than desmopressin alone, with lower recurrence and minimal adverse effects.