Abstract： Objective： To observe the clinical efficacy of Jieyu Tongqiao Prescription combined with scalp acupuncture in the treatment of post-stroke depression （PSD），and to observe its effects on serum levels of Apelin-13 and Claudin-5. Methods： A total of 120 patients with PSD admitted to Jiaxing Hospital of Traditional Chinese Medicine from January to December 2024 were enrolled and randomly divided into the combination group and the control group using the random number table method，with 60 cases in each group. During treatment，4 cases dropped out from the control group and 56 patients were finally included；6 cases dropped out from the combination group and 54 patients were finally included. Both groups received routine stroke treatment. The control group received additional scalp acupuncture，while the combination group received Jieyu Tongqiao Prescription on top of the control group′s regimen. After three months of treatment， the clinical efficacy of the two groups was evaluated. The following parameters were compared between the two groups： National Institutes of Health Stroke Scale （NIHSS） score， Hamilton Depression Scale 17 item version（HAMD-17） score，Pittsburgh Sleep Quality Index （PSQI） score，eye movement features （REM sleep latency， REM density）， serum levels of interleukin-6 （IL-6）， Apelin-13， Claudin-5， cortisol （COR）， brain-derived neurotrophic factor （BDNF）， and 5-hydroxytryptamine （5-HT）， as well as safety. Results： After treatment， the total effective rate was 90.74% （49/54） in the combination group and 76.79% （43/56） in the control group， with a statistically significant difference between the two groups （P＜0.05）. After treatment， the scores of NIHSS， HAMD-17， and PSQI decreased significantly in both groups compared with those before treatment （P＜ 0.05），and the scores of NIHSS，HAMD-17，and PSQI in the combination group were significantly lower than those in the control group （P＜0.05）. After treatment， REM sleep latency was increased （P＜0.05） and REM density was decreased （P＜0.05） in both groups compared to before treatment；the combination group showed longer REM latency and lower REM density than the control group （P＜0.05）. After treatment， serum levels of IL-6 and COR decreased significantly （P＜0.05），while levels of BDNF and 5-HT increased significantly （P＜0.05） in both groups compared with those before treatment；the combination group showed lower levels of IL-6 and COR （P＜0.05） and higher levels of BDNF and 5-HT （P＜0.05） than the control group. After treatment， serum levels of Apelin-13 and Claudin-5 increased significantly in both groups compared with those before treatment （P＜0.05）， and the levels of Apelin-13 and Claudin-5 in the combination group were significantly higher than those in the control group （P＜0.05）. During treatment， the incidence of adverse reactions was 9.26% （5/54） in the combination group and 12.50% （7/56） in the control group， with no significant difference between the two groups （P＞0.05）. No obvious abnormalities in routine blood tests or liver/kidney function were observed in either group. Conclusion：Jieyu Tongqiao Prescription combined with scalp acupuncture can improve PSD symptoms and enhance clinical efficacy through multiple pathways，including regulation of neurotransmitters，reduction of inflammation responses，and repair of the blood-brain barrier.