OBJECTIVES: To assess the efficacy and safety of once-weekly dulaglutide versus other oral antihyperglycemic medications in T2DM. METHODS: A literature search of the electronic databases of PubMed, EMBASE, and Cochrane libraries was conducted for randomized controlled trials (RCTs) comparing dulaglutide with other antihyperglycemic medications (excluding insulin) or placebo in type 2 diabetes mellitus (T2DM). The search strategy comprised MeSH terms of “dulaglutide” and “type 2 diabetes mellitus.” The primary outcome measure of interest was a change in glycated hemoglobin (HbA1c) levels from the baseline at the end of trial. The methodological quality of selected trials was assessed using the Jadad scale. An outcome was calculated as the weighted mean difference (WMD, a change from the baseline). Two reviewers independently conducted the trial selection, data extraction, and quality assessment. Heterogeneity was assessed using the chi-squared Q test.  RESULTS: A total of 5 RCTs evaluating 1401 patients with T2DM (698 in the intervention and 703 in the control group) were selected for this meta-analysis. Trials comparing dulaglutide with placebo, metformin, and liraglutide varied in duration and dose of dulaglutide (0.5–1.5 mg daily). The results revealed that dulaglutide significantly lowered HbA1c levels compared with other antihyperglycemic medications and placebo (WMD = −0.978, 95% confidence interval = −1.702–−0.254) in patients with T2DM. In addition, a decline in fasting plasma glucose levels and a reduction in body weight were observed. Most commonly reported adverse events with dulaglutide were nausea, diarrhea, vomiting, hypoglycemia, injection-site reaction, and abdominal distention. All included trials demonstrated a high quality. CONCLUSIONS: Our results demonstrated the positive effects of dulaglutide on HbA1c levels, weight reduction, and fasting plasma glucose levels compared with other antihyperglycemic medications. Moreover, dulaglutide exhibited a favorable safety profile with minor adverse events. Additional well-designed, large RCTs are necessary to further support the clinical application of dulaglutide.