Liver cancer is among the most common types of cancer worldwide. The aim of the present study was to investigate whether the phosphatidylinositol‑3‑phosphate 5‑kinase (PIKfyve) inhibitor, YM201636, exerts anti‑proliferative effects on liver cancer. The methods used in the present study included MTT assay, flow cytometry, western blot analysis and an allograft mouse model of liver cancer. The results revealed that YM201636 inhibited the proliferation of HepG2 and Huh‑7 cells in a dose‑dependent manner. HepG2 and Huh‑7 cells exhibited strong monodansylcadaverine staining following treatment with YM201636. Accordingly, YM201636 treatment increased the expression of the autophagosome‑associated marker protein microtubule‑associated 1A/1B light chain 3‑II in HepG2 and Huh‑7 cells. The autophagy inhibitor 3‑methyladenine attenuated the inhibitory effects of YM201636 on liver cancer cell proliferation. Further in vivo analysis revealed that YM201636 (2 mg/kg) inhibited tumor growth without notable systemic toxicity. Mechanistic experiments demonstrated that YM201636 induced‑autophagy is dependent upon epidermal growth factor receptor (EGFR) overexpression in HepG2 and Huh‑7 cells. Collectively, these results suggested that the PIKfyve inhibitor YM201636 may inhibit tumor growth by promoting EGFR expression. This indicates that PIKfyve may be a potential therapeutic target for the treatment of liver cancer.