Ubiquitination is one of the major types of protein post-translational modifications. Proteins can be labeled with polyubiquitin chains through ubiquitination, which enables their recognition and subsequent degradation by the proteasome. Ubiquitination and deubiquitination are essential mechanisms for regulating the cell cycle process. Cell cycle-associated proteins, including various cyclins (CCNs), cyclin-dependent kinases (CDKs), and cyclin-dependent kinase inhibitors (CKIs), can all undergo ubiquitination. Recent studies have found that ubiquitin-specific proteases (USPs), members of the deubiquitinating enzyme (DUB) family, can inhibit the progression of liver cancer. USPs can reverse the ubiquitin-mediated degradation of proteins, thereby affecting apoptosis, autophagy, tumor signaling pathways, cell cycle regulation, DNA damage, and chemoresistance in liver cells, ultimately influencing the initiation and development of liver cancer. This article reviews recent research progress on the role of the DUB family member USPs in regulating the cell cycle of liver cancer cells, and their effects on tumor progression and chemoresistance, aiming to provide a reference for identifying new therapeutic targets for liver cancer treatment.