Parthenolide (PTL) is a sesquiterpene lactone compound obtained from Tanacetum parthenium (feverfew) and inhibits the activation of nuclear factor (NF)-κB. Epoxymicheliolide (EMCL) is a compound which is structurally related to PTL; however, EMCL is more stable under acidic and alkaline conditions. As a biologically active molecule, the detailed mechanism by which EMCL inhibits tumor activity remains to be elucidated. The present study evaluated the effect of EMCL on renal cell carcinoma (RCC) cells and identified the underlying mechanisms. It was found that treatment with EMCL significantly inhibited the proliferation of RCC cells in vitro and increased the induction of apoptosis by activating the mitochondria- and caspase-dependent pathway. Simultaneously, EMCL suppressed cell invasion and metastasis by inhibiting epithelial-mesenchymal transition, as observed in a microfluidic chip assay. Furthermore, using immunofluorescence analysis, an electrophoretic mobility shift assay and a dual-luciferase reporter assay, it was shown that treatment with EMCL significantly suppressed the expression of cyclooxygenase‑2 by inhibiting the translocation of NF‑κB p50/p65 and the activity of NF‑κB. Collectively, the results indicated that EMCL suppressed tumor growth by inhibiting the activation of NF‑κB and suggested that EMCL may be a novel anticancer agent in the treatment of RCC.