BACKGROUND: The accurate prognostication and recurrence monitoring of esophageal cancer (EC) are pivotal yet challenging. Despite the promising roles of squamous cell carcinoma antigen (SCC) and cytokeratin 19 fragment (CK19 Fragment) as cancer biomarkers in EC, their prognostic value remains unquantified. This meta-analysis is the first to quantitatively assess the relationship between serum levels of SCC and CK19 Fragment and EC prognosis, aiming to bridge this knowledge gap. METHODS: We conducted a comprehensive and systematic literature search across PubMed, Web of Science, Cochrane Library, and Embase databases, and Hazard ratios (HRs) and 95% confidence intervals (CIs) for overall survival (OS) and other survival outcomes were extracted and analyzed using random-effects or fixed-effects models depending on heterogeneity among the studies. RESULTS: 7309 patients from 29 studies were finally included in this meta-analysis. The quantitively summarized data revealed that elevated level of SCC and CK19 Fragment in serum was significantly correlated to poorer prognosis of EC patients with the pooled HR of OS was 1.25 (95%CI: 1.04-1.50, P < 0.05) and 1.69 (95%CI: 1.25-1.27, P < 0.05), respectively. Subgroup analyses indicated that the prognostic value of these biomarkers varied across different patient populations and treatment modalities. CONCLUSION: This meta-analysis demonstrated that SCC and CK19 Fragment levels in serum were both strong prognostic biomarkers of EC patients. The elevated level of SCC and CK19 Fragment in serum was significantly associated with worse survival outcomes, advocating for the integration of these biomarkers into prognostic assessments to improve decision-making processes in the management of EC. REGISTRATION NUMBER: CRD42022311617.