To assess the efficacy and safety of sodium-glucose co-transporter 2 (SGLT2) inhibitors plus a dipeptidyl peptidase-4 (DPP-4) inhibitor in patients with type 2 diabetes mellitus (T2DM), we performed a systematic review and meta-analysis of 14 randomized controlled trials (RCTs) involving 4828 patients. Compared with a DPP-4 inhibitor, SGLT2 inhibitor/DPP-4 inhibitor combination therapy was significantly associated with a decrease in glycaemic control (HbA1c, -0.71%; fasting plasma glucose [FPG], -25.62mg/dL; postprandial plasma glucose, -44.00mg/dL), body weight (-2.05kg) and systolic blood pressure (-5.90mm Hg), but an increase in total cholesterol (TC) of 3.24%, high-density lipoprotein of 6.15% and low-density lipoprotein of 2.55%. Adding a DPP-4 inhibitor to an SGLT2 inhibitor could reduce HbA1c by -0.31%, FPG by -8.94mg/dL, TC by -1.48% and triglycerides by -3.25%. Interestingly, low doses of an SGLT2 inhibitor in the combination has similar or even better efficacy in some aspects than high doses. Similar adverse events were observed for the combination therapy, with the exception of genital infection vs DPP-4 inhibitor (risk ratio [RR], 5.31) and consistent genital infection vs an SGLT2 inhibitor (RR, 0.61). Further studies are warranted to confirm these results.