BACKGROUND AND OBJECTIVE: As the global prevalence of type 2 diabetes mellitus (T2DM) continues to rise, addressing its associated health risks, including colorectal cancer (CRC), is important. This study examines the relationship between the use of glucagon-like peptide-1 receptor agonists (GLP-1RAs) and the risk of CRC in comparison with other antidiabetic therapies. METHODS: We conducted a systematic search of PubMed, Embase, and Web of Science up to August 10, 2024, following PRISMA guidelines. Data extraction and screening were performed using Nested Knowledge software. Meta-analysis random effect model pooled Risk ratios (RRs) calculated using was performed using R v4.4 statistical software g. The protocol was registered with PROSPERO. RESULTS: Out of 1825 identified studies, five met the inclusion criteria, involving 2,047,256 T2DM patients assessing CRC risk. GLP-1RAs were associated with a significant reduction in CRC risk compared to thiazolidinediones (RR: 0.82, 95% CI: 0.68-0.96), insulin (RR: 0.57, 95% CI: 0.32-0.81), and SGLT2 inhibitors (RR: 0.77, 95% CI: 0.59-0.95). Comparisons with sulfonylureas, DPP-4 inhibitors, and metformin were not statistically significant. A potential protective effect against alpha-glucosidase inhibitors was observed (RR: 0.59, 95% CI: 0.18-1.00) but requires further investigation. CONCLUSION: The use of GLP-1RAs in T2DM is linked to a reduced risk of CRC compared to several standard antidiabetic therapies. These findings underscore the importance of considering long-term cancer risks in diabetes management and highlight the need for continued research to fully understand the implications of GLP-1RA use in T2DM patients.