OBJECTIVE To evaluate the efficacy and safety of first-line treatments regimens for human epidermal growth factor receptor 2 （HER2）-positive advanced gastric cancer. METHODS Computer searches were conducted on databases such as Web of Science， Embase， CNKI， and VIP in both Chinese and English， and abstracts of papers from the annual meetings of the European Society of Oncology and the American Society of Clinical Oncology were screened. Collected randomized controlled trials （RCTs） on first-line treatment for HER2-positive advanced unresectable or metastatic gastric cancer or gastroesophageal junction adenocarcinoma patients， with a retrieval period from database establishment until April 1， 2025. A network meta-analysis was conducted by two researchers who independently screened literature， extracted data， and evaluated the risk of bias in the study. RESULTS A total of 5 RCTs involving 2 797 patients and encompassing 6 treatment regimens were ultimately included. In the assessment of overall survival， there was a trend towards survival benefit for trastuzumab combined with chemotherapy （Tra_chemo）， pertuzumab combined with trastuzumab and chemotherapy （Per_Tra_chemo）， high-dose trastuzumab combined with chemotherapy （TraHD_chemo）， lapatinib combined with chemotherapy （Lap_chemo）， and pembrolizumab combined with trastuzumab and chemotherapy （Pem_Tra_chemo） compared to chemotherapy alone （chemo）； however， the differences were not statistically significant （P＞0.05）； the top two treatment regimens in terms of the surface under the cumulative ranking curve （SUCRA） were Pem_Tra_chemo （77.8%） and TraHD_chemo （74.2%）. For progression-free survival， there was statistical significance between Per_Tra_chemo and chemo， Pem_Tra_chemo and chemo （P＜0.05）； the top two treatment regimens in terms of SUCRA were Per_Tra_chemo （83.0%） and Pem_Tra_chemo （82.8%）. Regarding objective response rate， there was statistical significance between Pem_Tra_chemo and chemo （P＜0.05）； the top two treatment regimens in terms of SUCRA were Pem_Tra_chemo（87.4%）and Per_Tra_chemo（72.2%）. In terms of safety， there was statistical significance in the incidence of any level of adverse events between Lap_chemo and chemo （P＜0.05）； the top two treatment regimens in terms of SUCRA were chemo（87.1%）and Pem_Tra_chemo（53.8%）. Lap_chemo exhibited a higher incidence of grade ≥3 adverse events compared to chemo， and Per_Tra_chemo showed a higher incidence compared to Tra_chemo （P＜0.05）； the top two treatment regimens in terms of SUCRA were Tra_chemo （79.0%） and chemo （77.6%）. CONCLUSIONS In the first-line treatment of HER2-positive advanced gastric cancer， Pem_Tra_chemo and Per_Tra_chemo regimens have relatively good efficacy， but the safety risks are relatively high， requiring close attention and whole- process management.