Oxaliplatin (OXA) is a first‑line chemotherapy agent for hepatocellular carcinoma (HCC); however, its application is hindered by low therapeutic sensitivity and severe adverse effects. Acteoside (ACT) has both antitumor and hepatoprotective properties. Therefore, the present study investigated the mechanisms underlying the synergistic and toxicity‑reducing effects of ACT as an adjuvant to OXA in HCC therapy. Liver cancer cell lines and a xenograft mouse model were treated with ACT and/or OXA. In vitro Cell Counting kit‑8, Transwell invasive assay, wound healing assay, cell cycle and apoptosis detection assays assessed cell viability, migration, invasion, cell cycle progression and apoptosis to evaluate the synergistic effects of the combination therapy. In vivo studies examined tumor growth, cell proliferation, survival time and blood biochemical indices. The effects of ACT on OXA‑induced toxicity were also evaluated. Transcriptomics and metabolomics analyses were integrated to elucidate the mechanisms by which ACT enhances OXA efficacy and mitigates its toxicities. The results revealed that ACT synergized with OXA to inhibit HCC progression both in vivo and in vitro. ACT significantly alleviated OXA‑induced toxicity, particularly neurotoxicity. Mechanistically, phosphatidylinositol signaling system‑associated genes/proteins exerted important roles in the anti‑HCC effects of ACT. Western blotting revealed that ACT‑induced upregulation of INPP4B inhibited the PI3K/AKT signaling pathway, which may underlie its ability to enhance the therapeutic efficacy of OXA and reduce its toxic effects. In conclusion, ACT enhanced efficacy and reduced the toxicity of OXA in the treatment of HCC, potentially via the regulation of INPP4B to inhibit the PI3K/AKT signaling pathway.