Cholangiocarcinoma (CCA) is the second most common hepatobiliary cancer after hepatocellular carcinoma. Antiangiogenic therapy has been administered to patients with CCA, but the benefits of this therapy remain unsatisfactory. Improved understanding of the molecular mechanisms underlying angiogenesis in CCA is required. In the present study, the expression of GATA‑binding protein 6 (GATA6), lysyl oxidase‑like 2 (LOXL2) and vascular endothelial growth factor A (VEGFA), in addition to the microvessel density (MVD), were evaluated by performing immunohistochemical staining of human CCA microarrays. The expression of GATA6/LOXL2 was associated with poor overall survival (P=0.01) and disease‑free survival (P=0.02), and was positively associated with VEGFA expression (P=0.02) and MVD (P=0.04). In vitro, western blotting, reverse transcription‑quantitative PCR analysis and ELISAs revealed that altered GATA6 and LOXL2 expression regulated the expression levels of secreted VEGFA. Co‑immunoprecipitation demonstrated a physical interaction between GATA6 and LOXL2 in CCA cell lines, and the scavenger receptor cysteine‑rich domain of LOXL2 interacted with GATA6, which regulated VEGFA mRNA expression and protein secretion, and promoted tube formation. In vivo analyses further revealed that GATA6/LOXL2 promoted VEGFA expression, angiogenesis and tumor growth. The GATA6/LOXL2 complex represents a novel candidate prognostic marker for stratifying patients with CCA. Drugs targeting this complex may possess great therapeutic value in the treatment of CCA.