Ubiquitin-specific protease 5 (USP5), a member of the ubiquitin-specific proteases (USPs) family, functions by specifically removing ubiquitin chains from target proteins for stabilization and degrading unbound polyubiquitin chains to maintain a steady-state monoubiquitin pool. Ubiquitin-specific protease 5 regulates various cellular activities, including DNA double-strand break repair, transmission of neuropathic and inflammatory pain signals, immune response, and tumor cell proliferation. Furthermore, USP5 is involved in the development of multiple tumors such as liver, lung, pancreatic, and breast cancers as well as melanoma. Downstream regulatory mechanisms associated with USP5 are complex and diverse. Ubiquitin-specific protease 5 has been revealed as an emerging target for tumor treatment. This study has introduced some molecules upstream to control the expression of USP5 at the levels of transcription, translation, and post-translation. Furthermore, the study incorporated inhibitors known to be associated with USP5, including partially selective deubiquitinase (DUB) inhibitors such as WP1130, EOAI3402143, vialinin A, and chalcone derivatives. It also included the ubiquitin-activating enzyme E1 inhibitor, PYR-41. These small molecule inhibitors impact the occurrence and development of various tumors. Therefore, this article comprehensively reviews the pivotal role of USP5 in different signaling pathways during tumor progression and resumes the progress made in developing USP5 inhibitors, providing a theoretical foundation for their clinical translation.