Background: Cholangiocarcinoma is a malignant tumor originating from the bile duct epithelium. Metastasis is an important factor affecting the prognosis of cholangiocarcinoma. To explore the role and mechanism of calcium-activated chloride channel protein Tweety homolog 3 (TTYH3) in cholangiocarcinoma metastasis. Methods: TTYH3 was overexpressed and knocked down in cholangiocarcinoma cells, and in vitro experiments were performed to clarify the biological function of TTYH3 in cholangiocarcinoma. Experiments on xenograft tumor mice model have shown that TTYH3 promotes tumorigenesis of cholangiocarcinoma cells. Analysis of the relationship between TTYH3 expression and patient prognosis and lymph node metastasis in cholangiocarcinoma tissue specimens. Exosomes were extracted from bile of patients with cholangiocarcinoma and bile duct stones, and the expression of TTYH3 in exosomes was compared. TTYH3 overexpressed exosomes were used to treat endothelial cells, and their function and mechanism in promoting lymphangiogenesis were analyzed. Results: In vitro experiments confirmed that TTYH3 promoted the migration and invasion of cholangiocarcinoma cell line QBC939. In vivo experiments confirmed that TTYH3 promotes the tumorigenesis of cholangiocarcinoma cells. TTYH3 promotes epithelial-to-mesenchymal transition of cholangiocarcinoma cells through the Wnt/β-catenin signaling pathway. TTYH3 promotes cholangiocarcinoma cell self-expression through positive feedback. TTYH3 is highly expressed in cholangiocarcinoma tissues. Patients with high TTYH3 expression have poor prognosis and a high incidence of lymph node metastasis. The TTYH3 protein content of bile exosomes in patients with cholangiocarcinoma is increased, which promotes the invasion and metastasis of cholangiocarcinoma cells, while also promoting lymphangiogenesis and increased permeability. TTYH3 promotes the uptake of exosomes by lymphatic cells and promotes lymphangiogenesis by regulating the influx of calcium ions and chloride ions in lymphatic cells. Conclusions: TTYH3 promotes the invasion and metastasis of cholangiocarcinoma cells through the Wnt/β-catenin signaling pathway, and exosome TTYH3 promotes lymphangiogenesis and lymph node metastasis.