BACKGROUND: Patients with advanced cholangiocarcinoma (CCA) often experience malignant obstructive jaundice (MOJ), which significantly impacts both their quality of life and prognosis. Recent studies suggest that the addition of iodine-125 (125I) radioactive seeds during stent placement may improve stent patency and extend patient survival. However, the conclusions drawn from different studies remain inconsistent, and there is a lack of a systematic assessment to better clarify the clinical benefits of this treatment. OBJECTIVE: To compare and evaluate the efficacy and safety of biliary stenting combined with intraluminal 125I seed brachytherapy versus biliary stenting alone in patients with advanced CCA and MOJ. METHODS: A systematic search of databases (PubMed, Embase, Cochrane, Web of Science, Wanfang Data, CQVIP, China National Knowledge Infrastructure [CNKI], and Chinese Biomedical [CBM]) was conducted to identify studies published before June 2025 that compared stents with or without 125I seeds in the treatment of advanced CCA. The quality of the included studies was assessed using the Cochrane Collaboration's tool and the Newcastle-Ottawa Scale (NOS). The outcomes measured include overall survival, local control rate, tumor shrinkage, stent patency, stent obstruction, liver function, and complications. RESULTS: Fourteen studies, including six randomized controlled trials and eight retrospective cohort studies, with a total of 1,078 patients, were included in this meta-analysis. Of these, 564 patients were treated with biliary stenting combined with intraluminal 125I seed brachytherapy (group A), while 514 patients received conventional biliary stenting alone (group B). The pooled analysis revealed that group A had a significantly longer overall survival (P < 0.001) and stent patency (P < 0.001) compared to group B. No significant differences were observed between the two groups in the overall incidence of complications (P = 0.854), acute cholangitis (P = 0.464), biliary infection (P = 0.903) and hemobilia (P = 0.364). Additionally, no significant differences were found in post-treatment reductions of serum indices such as total bilirubin (P = 0.134), direct bilirubin (P = 0.946), alanine aminotransferase (P = 0.096) and aspartate aminotransferase (P = 0.304). Subgroup analyses based on the type of 125I seed stent and study design demonstrated consistent results across the different categories. CONCLUSION: Biliary stenting combined with intraluminal 125I seed brachytherapy improves overall survival and extends stent patency compared to conventional biliary stenting, without increasing complications and causing severe liver damage. Therefore, it can be considered an effective and safe treatment for advanced CCA and MOJ.