Objective: To evaluate the preventive effect of 13 drugs on colorectal cancer (CRC) and guide the clinical application of these drugs. Materials and methods: 5 databases were searched for RCTs and cohort studies. The Cochrane bias risk assessment tool and the NOS quality evaluation tool were used to evaluate the quality of the studies. The funnel plot was used to analyze publication bias. A network meta-analysis of the extracted data was conducted by using Stata16.0 software. Results: A total of 57 studies involving 82719 participants were included. The funnel plot showed no obvious publication bias. The network meta-analysis showed that allopurinol was found to have the best effect, followed by berberine, non-aspirin NSAIDs, statins, metformin, calcium, mesalazine, ursodeoxycholic acid, vitamin D, mercaptopurine, aspirin, folic acid, and eicosapentaenoic acid. Conclusions: The preventive effect of allopurinol on CRC was better than that of the other 13 drugs.