<p>Nasopharyngeal carcinoma (NPC) is a highly invasive and metastatic malignancy closely associated with genetic predisposition and environmental factors, such as Epstein-Barr virus (EBV) infection. Zinc finger protein 618 (ZNF618), a member of the zinc finger protein family, plays a critical role in transcriptional regulation, yet its specific function in NPC remains unclear. This study employed a multi-omics approach to systematically analyze the expression profile, clinical significance, and transcriptional regulatory mechanisms of ZNF618 in NPC. Our results demonstrated that ZNF618 was significantly overexpressed at both mRNA and protein levels in NPC tissues (<i>p</i> &lt; 0.05), and its high expression was strongly associated with poor patient prognosis (<i>p</i> &lt; 0.05). Gene set enrichment analysis (GSEA) revealed that ZNF618 was positively correlated with pathways related to head and neck squamous cell carcinoma, while negatively associated with immune-related pathways, such as cytokine–cytokine receptor interaction. Chromatin immunoprecipitation sequencing (ChIP-seq), combined with single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics (ST), identified ENAH as a potential target gene of ZNF618, and their co-expression patterns were further validated in NPC. AlphaFold3 simulation analysis revealed interaction between the ZNF618 protein and the promoter region of the <i>ENAH</i> gene. This study suggests that ZNF618 may promote NPC progression and metastasis by transcriptionally activating target genes like <i>ENAH</i>. The overexpression of ZNF618 could serve as a potential diagnostic and prognostic biomarker for NPC. These findings provide novel insights into the molecular mechanisms of NPC and lay the foundation for developing targeted therapeutic strategies. Further studies are warranted to validate the functional mechanisms and clinical applications of ZNF618.</p>