Ubiquitination and deubiquitination have emerged as pivotal regulators of the development of colorectal cancer (CRC). However, the precise role of USP48 in CRC tumorigenesis is poorly understood. In this study, immunohistochemistry, protein blotting, MTT assays, plate cloning, scratch assays, transwell assays, and Hoechst 33258 staining were utilized to assess the expression level of USP48 and its involvement in CRC. The interaction between USP48 and Transforming growth factor-β activated kinase-1(TAK1) was confirmed using co-IP. Additionally, the impact of deubiquitination on downstream signaling was determined through qRT-PCR. Furthermore, the associations between USP48 and tumor-associated macrophages within the tumor microenvironment were investigated using flow cytometry. The findings of our study demonstrated that USP48 expression is downregulated in CRC patients. Through deubiquitination, USP48 interacts with and stabilizes TAK1, leading to the inhibition of TAK1-triggered NF-κB activation and effectively suppresses CRC tumorigenesis. Moreover, this study showed a positive correlation between USP48 expression and M1-type TAM polarization, revealed the potential of USP48 as a molecular target for the effective treatment of CRC in the future.