Objective <p>To systematically evaluate the efficacy and safety of first-line therapies and first-line-based combination therapies for treating monosymptomatic nocturnal enuresis (MNE) in children using a network meta-analysis.</p> Methods <p>PubMed, Embase, the Cochrane Library, Scopus, Web of Science, and ClinicalTrials.gov were comprehensively searched to identify randomized controlled trials (RCTs) comparing either different first-line therapies or combination regimens involving first-line treatments versus monotherapy for MNE. Two researchers independently screened studies, extracted data according to predefined criteria, and assessed the methodological quality of the included trials. Data were analyzed using R software, with relative risk (RR) used as the effect size for dichotomous outcomes. The certainty of evidence was assessed using the Confidence in Network Meta-Analysis (CINeMA) approach.</p> Results <p>A total of 23 RCTs involving 2424 children and eight interventions were included. The network meta-analysis showed that desmopressin combined with oxybutynin, propiverine, solifenacin, or tolterodine was significantly more effective in achieving complete response (CR) than desmopressin monotherapy. Additionally, combinations of desmopressin with oxybutynin or tolterodine were superior to alarm monotherapy. No statistically significant differences were found among interventions regarding partial response (PR). For relapse rate, alarm monotherapy, desmopressin plus alarm, and desmopressin plus solifenacin were significantly better than desmopressin monotherapy. No significant differences in adverse events (AEs) were found across the interventions. In terms of CR, the top three interventions were desmopressin plus oxybutynin, desmopressin plus tolterodine, and desmopressin plus solifenacin. For PR, the leading treatments were desmopressin plus oxybutynin, desmopressin monotherapy, and alarm therapy. Regarding relapse rate, desmopressin plus solifenacin, alarm therapy, and desmopressin plus tolterodine ranked highest. For AEs, alarm therapy, desmopressin plus propiverine, and desmopressin monotherapy had the lowest incidence. The certainty of evidence for the primary outcome ranged from moderate to low according to the CINeMA assessment.</p> Conclusion <p>Desmopressin combined with anticholinergic agents significantly improved CR versus desmopressin monotherapy and demonstrated partial significant superiority over alarm therapy alone. Among these, desmopressin plus oxybutynin demonstrated the best overall efficacy. Alarm therapy and desmopressin alone showed similar therapeutic effectiveness. Desmopressin monotherapy was associated with a higher relapse rate. Importantly, combination therapy did not significantly increase the risk of AEs compared to monotherapies. According to the CINeMA framework, the certainty of evidence was mostly low to moderate, highlighting the need for cautious interpretation and further high-quality trials.</p> Graphical abstract <p></p>