The forkhead transcription factor FOXK2 has been implicated in the progression of human cancers, but its role and clinical significance in hepatocellular carcinoma (HCC) have not been explored. Here we showed that FOXK2 expression was increased and associated with tumor size, TNM stage and vascular invasion. High FOXK2 expression was correlated with poor overall and disease-free survival in two independent cohorts consisting of 864 patients with HCC. The prognostic value of FOXK2 was validated by stratified survival analyses in subgroups difined by factors contributing to worse survival. Multivariate Cox regression model revealed that FOXK2 served as an independent factor for overall survival. The FOXK2 expression was reversely connected with miR-1271-5p in clinical samples. Re-introduction of miR-1271 decreased FOXK2 at both mRNA and protein levels. Luciferase assay confirmed that FOXK2 was a direct target of miR-1271 in HCC cells. Overexpression of FOXK2 enhanced the cell growth and migration, whereas FOXK2 silence resulted in the opposite phenotypes. Further studies demonstrated that FOXK2 exerted oncogenic activity via activation of PI3K/AKT signaling pathway. Collectively, our data suggest FOXK2 as an oncogene and a promising prognostic biomarker in HCC. Targeting the newly identified miR-1271/FOXK2/AKT axis may represent a potential strategy for HCC intervention.