Emerging studies have suggested that exportin-1 (XPO1) plays a pivotal role in hepatocellular carcinoma (HCC). However, the underlying mechanism of XPO1 in HCC sorafenib resistance remains enigmatic. The expression of XPO1 in HCC tumor tissues and sorafenib-resistant (SR) cells were analyzed by bioinformatics analysis, immunohistochemistry (IHC) and Western blotting. The interaction mechanism between XPO1 and Nucleophosmin (NPM1) was investigated by immunoprecipitation (IP), Mass-spectrometric (MS) analysis, immunofluorescence colocalization, CRISPR/CAS9 technology and RNA-seq. Analyses were also conducted on KPT-8602 and sorafenib's combined therapeutic effect. Our findings unraveled that the XPO1 overexpression was observed in HCC, and correlated with poorer survival. Knockdown of XPO1 inhibited the migration and proliferation of HCC cells, and also reduced the resistance of HCC cells to sorafenib. Mechanistically, XPO1 interacted with the C-terminus of NPM1 and mediated the acetylation of NPM1 at lysine 54 to maintain sorafenib resistance. XPO1 was bound to Vimentin, resulting in the epithelial-mesenchymal transition (EMT) progression in sorafenib-resistant cells. KPT-8602 in combination with sorafenib suppressed the tumor growth. These results highlighted the therapeutic value of targeting XPO1 in overcoming sorafenib resistance. The combinational treatment of KPT-8602 and sorafenib might be an improved therapeutic option.