Phosphoglycerate mutase 2 (PGAM2) is a crucial glycolytic enzyme. Recently, we have found that both the protein and acetylation levels of PGAM2 are down-regulated in hepatocellular carcinoma (HCC) tissues. However, the functional significance of PGAM2 in HCC progression remains poorly characterized. In this study, we demonstrated that PGAM2 functioned as a tumor suppressor in HCC progression, and knockdown of PGAM2 promoted proliferation of HCC cells and tumor growth both in vitro and in vivo. Moreover, we identified lysine 100 (K100) in PGAM2 as the predominant deacetylation site of sirtuin-2 (SIRT2), and that deacetylation of K100 destabilized PGAM2 by promoting its ubiquitination and degradation. Importantly, we discovered that PGAM2 suppressed aerobic glycolysis through an enzymatic activity-independent mechanism in HCC cells. Mechanistic investigations revealed that PGAM2 knockdown upregulated lactate dehydrogenase A (LDHA) expression via activation of the signal transducer and activator of transcription 3 (STAT3). Furthermore, we found that knockdown of PGAM2 sensitized HCC cells to sorafenib treatment. In conclusion, these findings elucidate the tumor-suppressive role of PGAM2 in HCC progression and its post-translational regulation through SIRT2-mediated deacetylation, which provide novel biomarkers and therapeutic targets for HCC treatment.