Abstract Background G protein-coupled receptors (GPCRs) mediate the intracellular signals that drive tumor development. Regulator of G protein signaling 14 (RGS14), a key negative regulator of GPCR signaling, influences liver injury, fat metabolism, and inflammation. However, the role of RGS14 in hepatocellular carcinoma (HCC) progression and its underlying mechanisms remain unclear. Methods In this study, we compared three pairs of HCC tissues and matched portal vein tumor thrombus (PVTT) samples using 4D-FastDIA proteomics to identify differentially expressed proteins. The clinical significance of RGS14 expression was further evaluated in HCC patient cohorts. Stable RGS14-overexpressing/knockdown cell models were established for functional assays (CCK-8, colony formation, Transwell, and wound healing assays). Additionally, tumor proliferation was evaluated through in vivo studies using a subcutaneous xenograft mouse model. RNA sequencing and western blot analysis were subsequently applied to validate the potential downstream signaling pathways. Results The results revealed that RGS14 was overexpressed in HCC tissues, which was correlated with adverse clinical outcomes. We also confirmed that RGS14 increased the proliferation, colony formation, migration, and invasion and promoted the epithelial‒mesenchymal transition (EMT) of HCC cells both in vitro and in vivo. Mechanistically, RGS14 elevated intracellular cAMP levels, activating the PKA/CREB axis to drive HCC progression. Conclusion Our findings suggest that RGS14 plays a critical oncogenic role in HCC by regulating cAMP/PKA/CREB pathway activation, underscoring its potential as both a prognostic marker and therapeutic target for HCC patients.