Metastasis-associated in colon cancer-1 (MACC1) is a newly identified gene that is involved in the development and progression of hepatocellular carcinoma (HCC), however its investigation has not been comprehensive. In the present study, in vitro techniques, including immunohistochemistry, western blotting, reverse transcription quantitative polymerase chain reaction, metabolic assay, MTT assay, colony formation assay and prognostic analysis were used to confirm the involvement of MACC1 in HCC. Histological examination confirmed that the protein expression of MACC1 was upregulated in HCC and was associated with the hexokinase-2 (HK2) protein, which also indicates a poor prognosis. Knockdown of MACC1 induced the reduction of glycogen consumption and lactate production, which then lead to a marked reduction of proliferation in the MHCC-97H cells. However, the overexpression of MACC1 produced the opposite results in the HepG2 cells. These results suggested that MACC1 leads to a poor prognosis in HCC, partly by promoting proliferation via enhancement in glucose metabolism by HK2. Therefore, this pathway has the potential to become an important therapeutic target in HCC.