Epidermal growth factor receptor (EGFR) is considered to play tumor-promoting role in esophageal cancer (EC). However, the underlying molecular mechanisms of EGFR-mediated EC progression and radioresistance still need to be further revealed. The mRNA and protein levels of EGFR and transcription factor AP-2 alpha (TFAP2A) in EC tissues and cells were tested by qRT-PCR and western blot. Cell migration, invasion, apoptosis, and radiosensitivity were detected by transwell assay, flow cytometry, and colony formation assay. The protein level of γH2AX and the number of γH2AX-foci were examined using western blot and immunofluorescence staining. The interaction between TFAP2A and EGFR promoter was evaluated using ChIP assay and dual-luciferase reporter assay. The ratio of p-ERK1/2/ERK1/2 was assessed by western blot. Animal study was performed to measure the effect of TFAP2A knockdown on EC tumor growth and radiosensitivity. EGFR had increased expression in EC tissues and cells. EGFR knockdown suppressed EC cell migration and invasion, while promoted apoptosis and radiosensitivity. TFAP2A was upregulated in EC, and it could bind to EGFR promoter region to activate EGFR transcription. Silencing of TFAP2A restrained EC cell metastasis, enhanced apoptosis, and radiosensitivity, while these effects were abolished by EGFR overexpression. TFAP2A promoted EGFR expression to activate ERK1/2 pathway. Also, interference of TFAP2A reduced EC tumorigenesis and enhanced radiosensitivity in mice models by decreasing EGFR expression. TFAP2A-activated EGFR promoted EC cell metastasis and radioresistance via regulating ERK1/2 pathway, providing a new idea for EC treatment.