Liver fibrosis is characterized by the excessive deposition of extracellular matrix proteins including collagen that occurs in most types of chronic liver disease. Even though our knowledge of the cellular and molecular mechanisms of liver fibrosis has deeply improved in the last years, therapeutic approaches for liver fibrosis remain limited. Profiling and characterization of the post-translational modifications (PTMs) of proteins, and more specifically NEDDylation and SUMOylation ubiquitin-like (Ubls) modifications, can provide a better understanding of the liver fibrosis pathology as well as novel and more effective therapeutic approaches. On this basis, in the last years, several studies have described how changes in the intermediates of the Ubl cascades are altered during liver fibrosis and how specific targeting of particular enzymes mediating these ubiquitin-like modifications can improve liver fibrosis, mainly in in vitro models of hepatic stellate cells, the main fibrogenic cell type, and in pre-clinical mouse models of liver fibrosis. The development of novel inhibitors of the Ubl modifications as well as novel strategies to assess the modified proteome can provide new insights into the overall role of Ubl modifications in liver fibrosis.