Abstract: Circular RNAs (circRNAs) are a class of noncoding RNA molecules with a covalently enclosed circular structure and are more stable than linear RNAs. CircRNAs possess unique characteristics and biological functions, playing key roles in the occurrence and development, proliferation, metastasis, invasion, and drug resistance of various types of cancer. Protein ubiquitination modification regulates the stability and functions of proteins through the ubiquitin-proteasome system (UPS), and affecting tumor-related signal transduction pathways. Interactions between circRNAs and UPS in cancer have attracted considerable interest. They may be novel biomarkers for cancer therapy and potential targets for mitigating tumors’ drug resistance. This article systematically reviews the molecular mechanism and clinical translational potential of circRNAs and protein ubiquitination modification in cancer and discusses their application prospects in diagnosis, treatment prognosis and overcoming drug resistance.