Colorectal cancer (CRC) is the third most prevalent malignancy worldwide and the second leading cause of cancer-associated deaths, posing a significant threat to human health. Given the limited therapeutic options and poor prognosis associated with CRC, there is an urgent need to develop new targeted therapeutic strategies to enhance clinical outcomes. The ubiquitin–proteasome system (UPS), a central regulator for cellular protein homeostasis, plays a pivotal role in the initiation and progression of CRC. The UPS modulates several essential signaling pathways and is involved in regulating tumor immunity and resistance to chemotherapy. Thus, the UPS contributes significantly to the complex biological processes underlying CRC pathogenesis. In recent years, small-molecule compounds targeting the UPS have exhibited considerable therapeutic potential in CRC treatment. These drugs intervene in crucial steps in the UPS, such as the activity of E1, E2, and E3 enzymes, or directly target the proteasome, thereby regulating the degradation of oncogenic proteins and effectively impeding tumor progression. Moreover, emerging therapeutic strategies such as proteolysis-targeting chimera (PROTAC) and molecular glue technologies selectively degrade specific oncogenic proteins, thereby offering new avenues and promising opportunities for CRC treatment.