The pyruvate kinase M2 isoform (PKM2) is a key component of aerobic glycolysis and has been reported to regulate apoptosis. However, it is unclear whether PKM2 is involved in cyclooxygenase‑2 (COX‑2) induced apoptosis‑resistance in hepatocellular carcinoma (HCC) cells. In the present study, it was observed that COX‑2 and PKM2 were significantly elevated in hepatocellular carcinoma tissues compared with adjacent liver tissues (P<0.05). Furthermore, their expression was positively associated with worse clinicopathological characteristics, which indicates poor prognosis in patients with HCC. COX‑2 knockdown significantly reduced the expression of PKM2 and hypoxia inducible factor‑1α (HIF‑1α) at the mRNA and protein levels in addition to inhibiting proliferation (P<0.05), whereas apoptosis was notably increased. Furthermore, HIF‑1α and PKM2‑knockdown increased cell apoptosis without inhibiting COX‑2 expression. PKM2 inhibition did not have a marked effect on COX‑2 and HIF‑1α expression. In conclusion, the results of the present study suggested that HIF‑1α/PKM2 pathway‑associated metabolic changes may facilitate COX‑2‑induced apoptosis resistance in HCC cells.