Recent studies have reported a correlation between ubiquitination or deubiquitination and cancer development. But mechanisms underlying the roles of genes associated with E3 ubiquitin ligases and deubiquitinating enzymes (DUB) in liver cancer remain to be explored. We analyzed and screened differentially expressed genes related to E3 ubiquitin ligases and DUB in liver cancer on the basis of public databases. Cluster analysis was utilized to classify liver cancer samples into different subtypes. Survival analysis, immune analysis, and pathway enrichment analysis were performed on the subtypes. We constructed a protein-protein interaction network using STRING to screen hub genes. Finally, we used the Connectivity Map (CMap) database to predict targeted small molecules. The results show that a total of 139 differentially expressed E3/DUB genes in liver cancer were screened. Then, liver cancer was classified into two subtypes, cluster 1 and cluster 2, based on E3-related and DUB-related genes. Patients in cluster 1 had higher survival rates and immune levels than those in cluster 2. Four hub genes (RPSA, RPS5, RPL30, and RPL8) significantly affecting the survival of the two subtypes of liver cancer patients were identified based on cluster 1 and cluster 2. Finally, the CMap database predicted that small-molecule drugs including probenecid, dexamethasone, and etomidate may improve the prognosis of liver cancer patients. These findings may offer a reference for risk stratification studies and drug development in liver cancer.