Abstract: The ubiquitin-proteasome pathway is the primary regulator of intracellular protein degradation. In recent years, it has been found that multiple members of the deubiquitinating enzyme family play an important role in the development of liver cancer. The deubiquitinating enzymes remove ubiquitin chains of substrate proteins to maintain their stability; thus, they affect tumor progression via maintaining the stability of proteins involved in cell apoptosis, autophagy, cell cycle regulation, and DNA damage. Some small molecule inhibitors can exert an anti-tumor effect by inhibiting the activity of deubiquitinating enzymes. Here, we have reviewed research regarding deubiquitinating enzymes and their small molecule inhibitors in order to provide a new theoretical foundation for exploring novel and effective therapeutic targets for liver cancer.