Background: Nuclear receptor coactivator 6 (NCoA6) is overexpressed in various cancers and considered a multifunctional coactivator of various transcription factors and nuclear receptors. However, the role of NCoA6 in pancreatic ductal adenocarcinoma (PDAC) remains unclear.Methods: NCoA6 expression data in PDAC were extracted from TCGA and GTEx databases, and their correlation with survival outcomes were analyzed using the Kaplan-Meier plotter database. NCoA6 protein expression in PDAC tissues was evaluated using immunohistochemistry. RNA-sequencing technology was used to sequence the transcriptome of NCoA6-silenced PANC-1 cells, followed by differential expression, GO/KEGG and GSEA analyses. The effects of NCoA6 on cell proliferation, migration, invasion, cell cycle, and apoptosis were determined in two representative cell lines (PANC-1 and SW1990). Western blotting, qPCR, and co-immunoprecipitation were performed to explore the mechanism of action of NCoA6 in PDAC cells.Results: NCoA6 expression was markedly increased in PDAC tissues, and high NCoA6 expression was associated with poor survival prognosis. However, there was no significant relationship between NCoA6 expression and metastasis in PDAC patients. Our RNA-sequencing data analysis found 1194 significant differentially expressed genes between the control and NCoA6-silenced PANC-1 cells. GO/KEGG analysis results mainly focused on cytokine production, cytokine activity, and cytokine-cytokine receptor interactions. GSEA results showed that the knockdown of NCoA6 affected the expression of histone deacetylase 1 (HDAC1) targeted genes. NCoA6 knockdown suppressed proliferation, migration, and invasion of PDAC cells. Finally, western blotting, qPCR, and co-immunoprecipitation results showed that NCoA6 interacted with HDAC1 and that NCoA6 expression was negatively correlated with F-box and WD repeat domain-containing 7 (FBW7) and caudal-related homeobox transcription factor 2 (CDX2) expression in pancreatic cancer.Conclusions: NCoA6 has a profound effect on cell proliferation, migration, invasion, and prognosis of PDAC and is potentially related to the expression of HDAC1, FBW7, and CDX2. Our results may provide novel therapeutic strategies for PDAC patients.