Morphine is a typical opioid drug mostly used for relieving moderate to serious pain in the clinical. However, repeated or prolonged administration of morphine would develop antinociptive tolerance and drug dependence, thus greatly limiting its clinical application. Ubiquitin-proteasome pathway (UPP) is a major proteolytic pathway in the cell that plays a key role in many cellular processes. Studies have indicated that dysregulation of UPP might be an important mechanism in the development of morphine tolerance and dependence, thus, we will summarize the research progress in this paper. Understanding the effect of morphine on the regulation of UPP and its relationship with morphine-induced neural adaptive changes in the central nervous system is of great significance for further revealing the molecular mechanism of morphine tolerance and dependence.