<p>Patients with advanced hepatocellular carcinoma are treated using conventional therapeutic approaches and a variety of molecularly targeted drugs. Nevertheless, therapeutic resistance emerges because of the high heterogeneity of the malignancy, often restricting the effectiveness of these interventions. Therefore, therapeutic resistance represents a significant obstacle in managing liver cancer. Ubiquitination and deubiquitination, essential regulatory mechanisms, regulate the activity of diverse proteins and are pivotal in determining tumor therapeutic resistance. In this review, we focus on the enzymes involved in ubiquitination and deubiquitination in hepatocellular carcinoma, examining their associated phenotypes. Furthermore, we synthesize findings from a range of studies to elucidate the mechanisms of therapeutic resistance in hepatocellular carcinoma and highlight the critical role of ubiquitination and deubiquitination enzymes in these processes. Finally, we explore the therapeutic potential of targeting the ubiquitination and deubiquitination systems to enhance drug efficacy in liver cancer treatment significantly.</p>