<p>Ubiquitination, a key post-translational modification, is responsible for regulating protein stability, activity, subcellular localization, and interactions via the ubiquitin–proteasome system (UPS). The UPS plays a role in non-lysosomal protein degradation, involved in the coordinated action of ubiquitin-activating enzymes (E1s), ubiquitin-conjugating enzymes (E2s), and ubiquitin ligases (E3s). The review elaborates on the functions of key E3 ligases of MDM2, β-TrCP, and SCF complexes, which modulate cell cycle progression, apoptosis, metabolic reprogramming, and drug resistance in hepatocellular carcinoma (HCC). For instance, MDM2 promotes HCC development by degrading the tumor suppressor p53, while β-TrCP influences the Wnt/β-catenin signaling axis by changing β-catenin levels. Deubiquitinating enzymes (DUBs), including the USP family and CYLD, also play significant roles in HCC by stabilizing or destabilizing critical proteins involved in oncogenesis. The clinical potential of ubiquitination-related molecules as biomarkers for predicting HCC prognosis and as therapeutic targets is also discussed. This review comprehensively examines the role of ubiquitination modification in HCC and its clinical relevance. Future research directions include the exploration of novel ubiquitination modifications, their interactions with other post-translational modifications, and the development of precision medicine strategies based on multi-omics technologies to improve HCC treatment outcomes.</p> Graphical Abstract <p></p>