Whether a focal adhesion kinase (FAK)‑Krüppel‑like factor 8 (KLF8)‑matrix metalloproteinase (MMP)‑9/E‑cadherin signaling axis exists in hepatocellular carcinoma (HCC) remains unknown. In the present study, KLF8 expression and its clinicopathological significance in HCC was investigated to determine the correlation between KLF8 and FAK, MMP‑9 and E‑cadherin expression. Tissues were obtained from 60 surgically resected HCC and normal tumor‑adjacent tissues. KLF8, FAK, MMP‑9 and E‑cadherin expression levels were examined by quantitative real‑time reverse transcription polymerase chain reaction (qRT‑PCR) and immunohistochemistry. In addition, KLF8, FAK, MMP‑9 and E‑cadherin protein expression levels were examined by western blot analysis in 5 portal vein cancer emboli and corresponding HCC tissues. The clinicopathological data of the HCC patients were retrospectively analyzed. KLF8 mRNA expression was found to be significantly upregulated in HCC tumor tissues compared with normal tumor‑adjacent tissues (P<0.05). KLF8 protein was highly expressed in portal vein cancer emboli. KLF8 expression level was significantly higher in tumors with advanced TNM stages and vascular invasion compared with that in tumors with early TNM stage and absence of vascular invasion (P<0.05). KLF8 protein and mRNA expression in HCC positively correlated with that of FAK (r=0.362, P<0.001; and r=0.377, P<0.01, respectively) and MMP‑9 (r=0.392, P<0.01; and r=0.336, P<0.01, respectively), but negatively correlated with E‑cadherin (r=‑0.364, P<0.01; and r=‑0.410, P<0.01, respectively). Results of the current study highlight a novel FAK‑KLF8‑MMP‑9/E‑cadherin signaling axis during HCC progression.