In clinical practice, tumor occurrence and progression appear to be more frequent and rapid in patients with type 2 diabetes mellitus (T2DM) compared to non-diabetic individuals. Epidemiological studies have confirmed that the incidence of colorectal cancer (CRC) is relatively higher in patients with T2DM. However, the key candidate regulatory factors that mediate and drive the concurrent development and progression of T2DM and CRC remain unclear. Analysis using the Significant Bias Evaluation Method on clinical data revealed that patients with T2DM have a higher propensity for developing lung cancer, colorectal cancer, and breast cancer. Further analysis of the key factors associated with T2DM and related tumors identified GSK3β as a potential key regulatory factor in CRC development in T2DM patients, through differential expression analysis using the limma package on real-world data. Western blot and qRT-PCR validation revealed that, compared to the non-insulin-resistant HT29 CRC cell line group, the mRNA and protein expression levels of GSK3β were significantly elevated in the insulin-resistant group. Similarly, the mRNA and protein expression levels of factors associated with the GSK3β-β-catenin-CyclinD1/cMyc pathway were also upregulated. Furthermore, when GSK3β was silenced or overexpressed, the proliferative effect of tumor cells was markedly reduced or increased, respectively. In summary, GSK3β is upregulated in T2DM patients with CRC and contributes to tumor progression. GSK3β holds promise as a novel therapeutic target for the treatment of patients with T2DM complicated by CRC, potentially providing a solution to address clinical challenges.