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Simple Summary: Colorectal cancer (CRC) is the third most common cancer worldwide and the second leading cause of cancer-related death. In this study, we aimed to determine the biological function and regulatory mechanism of GMEB2 in CRC. We found that GMEB2 was highly expressed in CRC and significantly promoted the growth of CRC in vitro and in vivo. Mechanistically, GMEB2 acted as a transcription factor to activate ADRM1/NF-κB signalling and was upregulated by YTHDF1 through enhancing its mRNA stability. Our findings suggest that GMEB2 may serve as a new therapeutic target for CRC treatment in the future. Transcription factors are frequently aberrantly reactivated in various cancers, including colorectal cancer (CRC). However, as a transcription factor, the role of GMEB2 in cancer is still unclear, and further studies are needed. Here, we aimed to identify the function and mechanism of GMEB2 in regulating the malignant progression of CRC. GMEB2 was found to be highly expressed in online data analyses. We demonstrated that GMEB2 was markedly upregulated at both the mRNA and protein levels in CRC cells and tissues. GMEB2 knockdown inhibited CRC cell growth in vitro and in vivo. Mechanistically, as a transcription factor, GMEB2 transactivated the ADRM1 promoter to increase its transcription. Rescue experiments showed that ADRM1 downregulation partially reversed the promoting effects of GMEB2 on CRC growth in vitro. Moreover, the GMEB2/ADRM1 axis induced nuclear translocation of NF-κB, thus activating NF-κB signalling. Finally, we further revealed that YTHDF1 recognized and bound to the m6A site on GMEB2 mRNA, which enhanced its stability. Taken together, our findings reveal the crucial role and regulatory mechanism of GMEB2 in CRC for the first time and provide a novel potential therapeutic target for CRC therapy. [ABSTRACT FROM AUTHOR]