Increasing evidence highlights the critical roles of oxidative stress and endoplasmic reticulum (ER) stress in tumor initiation and progression. However, the specific functions of related genes in esophageal cancer (ESCA) remain poorly understood. To investigate the impact of oxidative and ER stress on ESCA, this study analyzed the TCGA and GEO databases to identify 12 oxidative stress-and ER stress-related differentially expressed genes (OERDEGs). Pathway analysis revealed significant enrichment in critical processes such as PRC2-mediated methylation, oxidative stress-induced senescence, and NOTCH signaling. A novel LASSO regression model was developed to link gene expression with clinical prognosis, and the model was validated through ROC and Cox regression analyses. Four OERDEGs (CDKN3, PINK1, SPP1, and TFRC) were identified as key biomarkers for ESCA prognosis. Notably, TFRC expression was significantly upregulated in ESCA cells under both oxidative and ER stress conditions, in a dose-and time-dependent manner. Functional assays confirmed that TFRC promotes cell proliferation, migration, and invasion by regulating the HIF-1 alpha and NOTCH1 signaling pathways. This study elucidates the complex interplay between oxidative/ER stress and ESCA progression and highlights the innovative application of bioinformatics to identify potential biomarkers for early diagnosis and therapeutic strategies. Targeting TFRC, in particular, may offer a novel approach to improving ESCA treatment and enhancing patient prognosis.