ABSTRACT Purpose The aquaporin‐9 (AQP9) has been implicated in tumorigenesis, but its pan‐cancer prognostic and immunology remain poorly understood. Therefore, we explored the role of AQP9 in pan‐cancer. Methods We systematically analyzed the expression of AQP9 across human cancers using multi‐omics data from The Cancer Genome Atlas (TCGA), Genotype‐Tissue Expression (GTEx), Oncomine and Tumor Immune Estimation Resource (TIMER2) database. Results AQP9 was overexpressed in most tumors, while its expression was reduced in cholangiocarcinoma (CHOL), hepatocellular carcinoma (LIHC), lung adenocarcinoma (LUAD), lung squamous carcinoma (LUSC) and prostate adenocarcinoma (PRAD). Survival analysis revealed that elevated AQP9 levels independently predicted poor prognosis in adrenocortical carcinoma (ACC), kidney renal clear cell carcinoma (KIRC), kidney renal papillary cell carcinoma (KIRP), lower‐grade glioma (LGG), and testicular germ cell tumors (TGCT). Importantly, AQP9 demonstrated significant correlations with tumor immune regulation, including associations with immune cell infiltration, cytokine activity, and immune checkpoint genes. Genomic alterations in AQP9 were linked to dysregulated immune pathways, and enrichment analysis highlighted its role in leukocyte migration and chemokine signaling. Furthermore, high AQP9 expression was associated with immunosuppressive tumor microenvironments, suggesting its potential to disrupt antitumor immunity. Conclusion Our findings suggest that elevated AQP9 levels were associated with poor prognosis and provide new insights into the dual role of AQP9 in tumor progression and immune evasion.