Clear cell renal cell carcinoma (ccRCC) is a highly aggressive subtype of renal cancer, often associated with poor prognosis and high mortality rates. In this study, we identified Nicotinamide N-methyltransferase (NNMT) as a key gene involved in the pathogenesis of ccRCC through RNA sequencing analysis of tumor and normal tissues from 14 patients. NNMT was among the top five upregulated genes, and its high expression was significantly correlated with reduced overall, progression-free, and disease-specific survival in patients, as well as advanced pathological stages and higher histologic grades. Gene ontology (GO) enrichment analysis revealed NNMT's role in biological processes such as signal transduction and immune response. Immune cell infiltration analysis indicated that high NNMT expression was associated with increased infiltration of activated NK cells and macrophages, while low expression correlated with a higher presence of regulatory T cells. Functional studies using siRNA-mediated NNMT knockdown in ccRCC cell lines demonstrated a significant reduction in cell proliferation, with further analysis revealing altered gene expression profiles related to cell adhesion and calcium ion binding. These findings suggest that NNMT not only plays a pivotal role in ccRCC aggressiveness but also may serve as a valuable prognostic biomarker and a potential therapeutic target for improving clinical outcomes in patients with this malignancy.