Background <p>Abnormal expression of zinc finger (ZNF) proteins is closely associated with tumor proliferation and metastasis. However, due to limited knowledge about ZNF83, we conducted a pan-cancer analysis to explore its shared and distinct roles across various human malignancies.</p> Method <p>Standardized TCGA pan-cancer data, encompassing clinical details and ZNF83 expression levels, were obtained for in-depth analysis. We assessed the expression landscape of ZNF83, explored its prognostic significance, and examined its relationship with tumor heterogeneity and cellular stemness. Furthermore, immunohistochemical analysis was performed on lung and kidney cancer tissues to support the bioinformatic findings.</p> Results <p>ZNF83 expression patterns vary markedly among tumor types, with transcriptomic analysis revealing upregulation in eight malignancies and significant downregulation in twenty-two, compared to adjacent non-cancerous tissues. Notably, ZNF83 levels exhibited robust associations with markers indicative of genomic instability and with indices of tumor stemness across multiple cancer types, suggesting a role in genome maintenance and cellular plasticity. Immunohistochemical staining further substantiated these findings, showing elevated ZNF83 protein levels in renal carcinoma samples, whereas reduced expression was observed in lung adenocarcinoma specimens. In renal cancer, higher ZNF83 expression correlated with poorer overall survival, reinforcing its prognostic value. Although the difference in lung adenocarcinoma was not statistically significant, the expression trend was consistent with transcriptomic observations from the TCGA database.</p> Conclusion <p>ZNF83 is differentially expressed across cancers and predicts poor prognosis, particularly in renal cell carcinoma, highlighting its utility as a prognostic biomarker.</p>