Objective: The zinc finger E-box binding homeobox (ZEB2), which can accelerate the nuclear DNA replication by inducing the activation of upstream transcription promoters, was widely considered as an oncogene. Recent study has found that the overexpression of ZEB2 is associated with a better prognosis in hepatocellular carcinoma. However, its roles in tumor growth, metastasis, and immunology are yet to be elucidated in COAD. Methods: The pan-cancer sequencing data was acquired from The Cancer Genome Atlas (TCGA)-Pan cancer cohort, normal human tissue data was acquired from the Genotype-tissue expression (GTEx) database, and Broad Institute Cancer Cell Line Encyclopedia (CCLE) were downloaded from UCSC Xena. We used the cBioPortal webtool to analyze and visualize the ZEB2 pan-cancer genomic alteration rate. GEO Expression Datasets were used to explore ZEB2 expression levels in COAD patients. UCSC Xena database was used to download prognostic information of COAD patients. The Cox regression and Kaplan–Meier analyses were used to assess the prognostic role of ZEB2 in COAD. Kyoto Encyclopedia of Genes and Genomes (KEGG) was performed to determine the biological pathways. Gene Ontology (GO) enrichment analysis was performed to determine the biological processes, molecular functions, and cellular components that were altered in a ZEB2-dependent manner in COAD. The module analysis of PPI interaction network was performed using the MCODE tool of Cytoscape software, and the characteristic molecules were selected by cytohHubba tool. CIBERSORTx database was used to analyze the ZEB2 expression in the presence of 22 types of immune infiltrating cells. Results: This study found that ZEB2 was aberrantly expressed in most cancer types, and it was significantly downregulated in COAD compared with normal tissue. In addition, our findings also show that overexpression of ZEB2 was associated with a better prognosis in COAD. Mechanistic analysis revealed that overexpression of ZEB2 was associated with the neutrophil extracellular trap formation in COAD. And the results show that ZEB2 expression was significantly correlated with several kinds of immune cell infiltration. Conclusion: This study demonstrates that overexpression of ZEB2 was associated with better prognoses in patients with COAD. ZEB2 has close relationship with ACTB, which was highly related to NETs. These findings suggest a dual role of ZEB2 in COAD growth, metastasis, and immunology.