Renal cell carcinoma (RCC) is the most common malignant disease of the kidneys in adults. Patients with metastatic RCC have an unusually poor prognosis and exhibit resistance to all current therapies. Therefore, it is necessary to explore novel molecules involved in the progression of RCC and to identify effective therapeutic targets. Hepatocyte nuclear factor‑4α (HNF‑4α) serves an important role in hepatocyte differentiation and is involved in the progression of liver cancer; however, the functional role of HNF‑4α has not been well established in RCC. The present study reported that HNF‑4α expression was markedly downregulated in RCC tissue samples compared with in normal controls by immunohistochemistry and RNA‑sequencing analysis. Statistical analysis demonstrated that HNF‑4α downregulation was significantly associated with tumor stage, recurrence, metastasis and poor prognosis in patients with RCC. Furthermore, wound‑healing and Transwell assays revealed that downregulation of HNF‑4α promoted cell migration and invasion by transcriptionally regulating E‑cadherin in RCC. Finally, a positive correlation was revealed between HNF‑4α expression and E‑cadherin expression, and patients with low E‑cadherin expression also had a poor prognosis. These findings may provide novel insights into the biological effects of HNF‑4α and lay the foundation for the discovery of molecular therapeutic targets in RCC.