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Cholangiocarcinoma (CCA) ranks as the second most prevalent primary malignant tumor of the liver with an extremely poor overall prognosis, and the five-year survival rate of patients remains merely 5%–15%. The incidence and mortality of CCA have kept rising globally in recent decades. Epidemiological projections indicate that its case load may increase tenfold within the next 20 to 30 years. At present, effective targeted therapies for CCA are severely limited. Accordingly, exploring innovative targeted strategies and improving the efficacy of chemotherapy and immunotherapy are critical to ameliorating clinical outcomes and breaking therapeutic bottlenecks for CCA patients. Human intrahepatic cholangiocarcinoma organoids are generated via in vitro culture of cells isolated from patients’ clinical tumor specimens, which can faithfully mimic the cellular biological properties, histopathological morphology and molecular signatures of primary tumors. As a high-performance preclinical research model, CCA organoids are capable of recapitulating tumor heterogeneity and tumor microenvironment features, establishing a stable in vitro system to systematically investigate the initiation, malignant progression and metastatic mechanisms of intrahepatic cholangiocarcinoma. Patient-derived organoids can sustainably preserve the core biological phenotypes of primary tumors over long-term culture, and are applicable to high-throughput drug screening and evaluation of individualized therapeutic efficacy. The drug response profiles of this model are highly consistent with patients’ clinical treatment outcomes, enabling accurate prediction of therapeutic effects and providing credible experimental evidence for designing individualized therapeutic regimens. Combined with CRISPR/Cas9 gene-editing technology, CCA organoids support specific knockout or overexpression of target genes, which facilitates the analysis of biological functions of key genes and the discovery of novel potential therapeutic targets for cholangiocarcinoma. Furthermore, CCA organoids can be co-cultured with various stromal cells including immune cells and cancer-associated fibroblasts to reconstruct the physiological tumor microenvironment in vitro. Such co-culture systems can effectively simulate the dynamic interactions between tumor-stroma and tumor-immune cells, offering vital support for elucidating tumor immune escape mechanisms and developing innovative immunotherapeutic strategies. Meanwhile, organoid models can be adopted to explore characteristic pathological mechanisms of CCA, analyze the crosstalk between tumors and the extracellular matrix, and clarify the specific metabolic disorders and aberrant signaling pathways during tumor progression. Hence, organoids serve as an innovative research platform for mechanistic studies and translational applications of cholangiocarcinoma.