Esophageal squamous cell carcinoma (ESCC) has a significantly low survival rate, primarily due to the lack of diagnostic markers for early diagnosis and effective therapies. Recently, CD98 has been proposed as a specific marker of mature esophageal basal cells, which may be associated with esophageal carcinogenesis. Therefore, we aimed to investigate the clinical significance and biological function of CD98 in ESCC progression, as well as the value of CD98 as a potential new marker for the early diagnosis of ESCC. Through MassARRAY system spectroscopy, DIA proteomics analysis, immunohistochemical and functional experiments, we found hypomethylation-linked upregulation of CD98 expression, which was associated with poor prognosis, promoted cell proliferation by regulating the cell cycle in ESCC. Furthermore, we not only demonstrated that the range of CD98 expression was consistent with that of dysplastic cells in 73.81% of low-grade intraepithelial neoplasia (LGIN) and 83.08% of high-grade intraepithelial neoplasia (HGIN) cases, but also confirmed the expression level of CD98 was positively correlated with the classical diagnosis marker P53. Compared to using P53 alone, the combination of the immunohistochemical markers CD98 and P53 (either one was positive) provided more accurate diagnostic data for LGIN (92.86% vs. 88.10%, p < 0.01) and HGIN (93.85% vs. 73.85%, p < 0.01). In summary, we propose that CD98 is involved in a crucial step in ESCC carcinogenesis, and when combined with P53, may serve as a diagnostic marker for ESCC precancerous lesions.