TFAP2A is a transcription factor that orchestrates a variety of cell processes, including cell growth and tissue differentiation. However, the regulation of TFAP2A in human nasopharyngeal carcinoma tumorigenesis and its precise mechanism of action remain largely unknown. In this study, we investigated the biologic role and clinical significance of TFAP2A in nasopharyngeal carcinoma growth and progression and identified the underlying molecular mechanisms. We found that TFAP2A was highly expressed in various nasopharyngeal carcinoma cell lines and tumor tissue specimens and was significantly correlated with hypoxia-inducible factor-1α (HIF-1α) expression. A positive correlation of TFAP2A overexpression with advanced tumor stage, local invasion, clinical progression, and poor prognosis of patients with nasopharyngeal carcinomas were also observed. Moreover, we found that knockdown of TFAP2A expression by siRNA significantly inhibited tumor cell growth in nasopharyngeal carcinoma cell lines and in a subcutaneous xenograft mouse model by targeting the HIF-1α-mediated VEGF/pigment epithelium-derived factor (PEDF) signaling pathway. Treatment of nasopharyngeal carcinoma cells with TFAP2A siRNA dramatically inhibited the expression and the release of VEGF protein but did not change the level of PEDF protein, resulting in a significant reduction of the ratio of VEGF/PEDF. Pretreatment with a HIF-1α siRNA did not significantly change the TFAP2A siRNA-mediated inhibition in cell viability. Our results indicate that TFAP2A regulates nasopharyngeal carcinoma growth and survival through the modulation of the HIF-1α-mediated VEGF/PEDF signaling pathway, and suggest that TFAP2A could be a potential prognostic biomarker and therapeutic target for nasopharyngeal carcinoma treatment.