Objectives To evaluate the risk of cancers of digestive system with incretin-based therapies among patients with type 2 diabetes mellitus. Research design and methods Medline, Embase, Cochrane Library and ClinicalTrials.gov databases were searched for randomized controlled clinical trials that compared incretin-based drugs with placebo or other antidiabetic drugs. Paired reviewers independently screened citations, extracted data and assessed risk of bias of included studies. Network meta-analysis was performed, followed by subgroup analysis. The Grading of Recommendations Assessment, Development and Evaluation system was used to assess the quality of evidence. Results A total of 84 studies (n=101 595) involving cancers of digestive system were identified (a median follow-up of 30 weeks). The risk of cancers of digestive system with incretin-based therapies was comparable with insulin (OR: 0.86, 95% CI 0.27 to 2.69), metformin (OR: 0.32, 95%CI 0.07 to 1.38), sodium-glucose co-transporter 2 (OR: 5.26, 95% CI 0.58 to 47.41), sulfonylureas (OR: 1.27, 95% CI 0.68 to 2.39), thiazolidinediones (OR: 0.42, 95% CI 0.13 to 1.42), alpha-glucosidase inhibitors (OR: 2.98, 95% CI 0.12 to 73.80), and placebo (OR: 0.87, 95% CI 0.71 to 1.05). The results of subgroup analysis based on the type of digestive system cancers indicated that incretin-based therapies did not increase the risk of gastrointestinal cancers, respectively. The results of subgroup analysis based on age, duration, mean HbA1c, trial duration, and sample size did not indicate the risk of digestive system cancers. Conclusions Moderate to high Grading of Recommendations Assessment, Development and Evaluation evidence suggests that incretin-based therapies were not associated with an increased risk of cancer of digestive system in patients with type 2 diabetes mellitus.