Background <p>Epithelial ovarian cancer (EOC) is an aggressive malignancy marked by late diagnosis, recurrence, and treatment resistance. Tumor-associated macrophages (TAMs) play pivotal role in EOC progression, particularly through polarization into the pro-tumorigenic M2 phenotype. Ubiquitin-specific protease 19 (USP19), a deubiquitinase implicated in oncogenesis, regulates immune responses via the NLRP3 inflammasome. However, its role in EOC remains unclear. This study aims to investigate the role of USP19 in EOC progression and TAM polarization.</p> Methods <p>The expression levels of USP19 and its subcellular localization were evaluated in human EOC cell lines C13K, SW626, and A2780 using RT-qPCR, Western blot, and immunofluorescence. <i>USP19</i> knockdown models were established in A2780 cells to assess the effects of USP19 on cell proliferation, migration, invasion, and macrophage polarization in co-culture systems. Cytokine levels, macrophage markers, and epithelial-mesenchymal transition (EMT) marker expression were analyzed using ELISA, flow cytometry, and Western blot, respectively.</p> Results <p>USP19 was significantly upregulated in EOC cells and predominantly localized in the cytoplasm, co-localizing with NLRP3. Knockdown of <i>USP19</i> inhibited proliferation, migration, invasion, and EMT marker expression in A2780 cells. Additionally, USP19 suppression promoted TAM polarization towards the pro-inflammatory M1 phenotype by enhancing the expression of IL-12 and CXCL10 while reducing M2 markers such as CD206. Dual-conditioned medium from <i>USP19</i>-deficient cells significantly mitigated the malignant phenotypes of EOC cells, indicating a disrupted TAM-mediated feedback loop.</p> Conclusion <p>USP19 drives EOC progression by promoting M2 macrophage polarization and suppressing NLRP3-mediated inflammatory responses. Targeting USP19 may represent a novel therapeutic strategy to modulate the tumor immune microenvironment and inhibit EOC progression.</p>