Esophageal squamous cell carcinoma (ESCC) has a high incidence and low survival rate, necessitating the identification of novel specific biomarkers. Centromere-associated proteins (CENPs) have been reported to be biomarkers for many cancers, but their roles in ESCC have seldom been investigated. Here, the potential clinical roles of CENPs in ESCC patients were demonstrated by a systematic bioinformatics analysis. Most CENP-encoding genes were differentially expressed between tumor and normal tissues. CENPA, CENPE, CENPF, CENPI, CENPM, CENPN, CENPQ, and CENPR were upregulated universally in the three datasets. Survival analysis demonstrated that high expression of CENPE and CENPQ was positively correlated with the outcomes of ESCC patients. The CENPE-based forecast model was more accurate than the tumor-node-metastasis (TNM) staging-based model, which was classified as stage I/II vs. III/IV. More importantly, the forecast model based on the commonly upregulated CENPs exhibited a much higher area under the curve (AUC) value (0.855) than the currently known TTL, ZNF750, AC016205.1, and BOLA3 biomarkers. The nomogram model integrating the CENPs, TNM stage, and sex was highly accurate in the prognosis of ESCC patients ( AUC = 0.906 ). Besides, gene set enrichment analysis (GSEA) demonstrated that CENPE expression is significantly correlated with cell cycle, G2/M checkpoint, mitotic spindle, p53, etc. Finally, in validation experiments, we also found that CENPE and CENPQ were significantly overexpressed in esophageal cancer cells. Taken together, these results clearly suggest that CENPs are clinically promising diagnostic and prognostic biomarkers for ESCC patients.