Different anti-diabetic medications (ADMs) may modify cancer risk and mortality in patients with diabetes. We conducted a systematic review and meta-analysis to estimate the magnitude of association and quality of supporting evidence for each ADM. A total of 265 studies (44 cohort studies, 39 case-control studies, and 182 randomized controlled trials (RCT)) were identified, involving approximately 7.6 million and 137,540 patients with diabetes for observational studies and RCTs, respectively. The risk of bias overall was moderate. Meta-analysis demonstrated that the use of metformin or thiazolidinediones was associated with a lower risk of cancer incidence (RR = 0.86, 95% CI 0.83-0.90, I(2) = 88.61%; RR = 0.93, 95% CI 0.91-0.96, I(2) = 0.00% respectively). On the other hand, insulin, sulfonylureas and alpha glucosidase inhibitor use was associated with an increased risk of cancer incidence (RR = 1.21, 95% CI 1.08-1.36, I(2) = 96.31%; RR = 1.20, 95% CI 1.13-1.27, I(2) = 95.02%; RR = 1.10, 95% CI 1.05-1.15, I(2) = 0.00% respectively). Use of other types of ADMs was not significantly associated with cancer risk. This study indicates that some ADMs may modify the risk of cancer in individuals with diabetes. Knowledge of this risk may affect the choice of ADM in individuals concerned about cancer or at increased risk for cancer.