Liver cancer remains one of the leading causes of cancer deaths worldwide. The therapeutic effect of oxaliplatin on liver cancer is often limited by acquired resistance of the cancer cells. Abnormal activation of the PI3K/AKT pathway plays an important role in the acquired resistance of oxaliplatin. The present study investigated the effects of the PI3K inhibitor LY‑294002 and AKT inhibitor MK2206 on the chemosensitivity of oxaliplatin‑resistant liver cancer cells and the molecular mechanism involved. An oxaliplatin‑resistant liver cancer cell line HepG2 R was developed. MTT assay, clone formation experiments, flow cytometry and Annexin V‑FITC/PI staining were used to determine the proliferation, cycle and apoptosis of HepG2 R cells when oxaliplatin was combined with LY‑294002 or MK2206 treatment. The effects of LY‑294002 and MK‑2206 on the abnormal activation of PI3K/AKT pathway and hypoxia inducible factor (HIF)‑1α protein level in HepG2 R cells were detected using western blotting. The results indicated that the PI3K/AKT pathway is stably activated in HepG2 R cells. Compared with the AKT inhibitor MK2206, the PI3K inhibitor LY‑294002 more effectively downregulated the phosphorylation levels of p85, p110α, p110β, p110γ and AKT in the PI3K/AKT pathway in HepG2 R cells, and more effectively inhibited the proliferation of the cells. LY‑294002 enhanced the chemotherapy sensitivity of HepG2R cells to oxaliplatin by inducing G 0/G 1 phase arrest and increasing the proportion of apoptotic cells. In addition, LY‑294002 reduced the level of HIF‑1α, which is highly expressed in HepG2 R cells. It was concluded that LY‑294002 enhanced the chemosensitivity of liver cancer cells to oxaliplatin by inhibiting the PI3K/AKT signaling pathway, which may be related to the inhibition of HIF‑1α expression. These findings may have clinical significance for the treatment of oxaliplatin‑resistant liver cancer.