Sorafenib is the first FDA-approved first-line targeted drug for advanced HCC. However, resistance to sorafenib is frequently observed in clinical practice, and the molecular mechanism remains largely unknown. Here, we found that PLEKHG5 (pleckstrin homology and RhoGEF domain containing G5), a RhoGEF, was highly upregulated in sorafenib-resistant cells. PLEKHG5 overexpression activated Rac1/AKT/NF-κB signaling and reduced sensitivity to sorafenib in HCC cells, while knockdown of PLEKHG5 increased sorafenib sensitivity. The increased PLEKHG5 was related to its acetylation level and protein stability. Histone deacetylase 2 (HDAC2) was found to directly interact with PLEKHG5 to deacetylate its lysine sites within the PH domain and consequently maintain its stability. Moreover, knockout of HDAC2 (HDAC2 KO) or selective HDAC2 inhibition reduced PLEKHG5 protein levels and thereby enhanced the sensitivity of HCC to sorafenib in vitro and in vivo, while overexpression of PLEKHG5 in HDAC2 KO cells reduced the sensitivity to sorafenib. Our work showed a novel mechanism: HDAC2-mediated PLEKHG5 posttranslational modification maintains sorafenib resistance. This is a proof-of-concept study on targeting HDAC2 and PLEKHG5 in sorafenib-treated HCC patients as a new pharmaceutical intervention for advanced HCC.