Objective To investigate the role of junction plakoglobin （JUP） in high-grade serous ovarian cancer （HGSOC） and its influence on SET domain bifurcated 1 （SETDB1）. Methods Human HGSOC cell lines with stable JUP overexpression or knockdown were established. The impact of JUP on cell proliferation， invasion， and migration was evaluated in vitro using colony formation， Transwell invasion， and wound healing assays. A subcutaneous xenograft model in nude mice was generated to dynamically monitor tumor growth and peritoneal nodule development， thereby elucidating the role of JUP in tumoral proliferation and metastasis. Co-immunoprecipitation （Co-IP） assays were performed to identify downstream molecules regulated by JUP. RT-qPCR， Western blotting， and histone methyltransferase activity assays were utilized to validate the influence of JUP on SETDB1 expression and enzymatic activity. Furthermore， rescue experiments were conducted to assess whether reconstitution of SETDB1 could reverse the malignant phenotypes induced by JUP knockdown in HGSOC cells. Results JUP was significantly overexpressed in high-grade serous ovarian cancer （HGSOC） tissues （P < 0.000 1）， and patients with elevated JUP expression exhibited a poorer prognosis （P < 0.05）. In vitro experiments demonstrated that JUP overexpression enhanced tumor cell proliferation， invasion， and migration， whereas JUP knockdown suppressed these malignant phenotypes （P < 0.01）. In vivo studies further confirmed that JUP promoted tumor growth and peritoneal metastasis. Mechanistic analyses revealed that JUP directly interacts with SETDB1 and enhances its methyltransferase activity； notably， the oncogenic effects induced by JUP overexpression were reversed upon SETDB1 knockdown （P < 0.05）. Conclusion JUP promotes the malignant progression of HGSOC by directly binding to and modulating the enzymatic activity of SETDB1， highlighting its potential as a therapeutic target for HGSOC.