ObjectiveTo systematically review the efficacy and safety of orlistat in the treatment of overweight and obese type 2 diabetes mellitus (T2DM). Methods PubMed, EMbase, The Cochrane Library, CNKI, WanFang Data and VIP databases were electronically searched to collect randomized controlled trials (RCTs) on the efficacy and safety of orlistat in the treatment of overweight and obese T2DM patients from inception to June 29th, 2022. Two reviewers independently screened the literature, extracted data and assessed the risk of bias of the included studies; then, meta-analysis was performed by using Stata 16.0 software. Results A total of 24 RCTs involving 3 702 patients were included. The results of meta-analysis showed that compared with control group, orlistat group could significantly decrease the levels of fasting blood glucose (WMD=1.04, 95%CI 0.80 to 1.29, P<0.001), 2h postprandial blood glucose (WMD=1.17, 95%CI 0.78 to 1.56, P<0.001) and hemoglobin A1c (WMD=0.84, 95%CI 0.51 to 1.17, P<0.001), and the levels of total cholesterol, triglyceride, low density lipoprotein, body weight and body mass index also significantly decreased (P<0.001). The incidence of adverse events such as increased defecation and abdominal pain of orlistat was slightly higher than that of control group; however, most could be self-healing.Conclusion Current evidence shows that orlistat can effectively and safely improve blood sugar, lipid index in overweight and obese T2DM patients. Due to limited quality and quantity of the included studies, more high-quality studies are needed to verify the above conclusion.