Aim To investigate the effect of dipeptidyl peptidase-4 inhibitor (DPP-4i) on serum creatinine (Cr) in patients with type 2 diabetes mellitus (T2DM). Methods A systematic search was performed across databases of PubMed, Embase, Cochrane Library and Web of Science, and randomized controlled trials (RCT) of DPP-4i therapy for regulating Cr in T2DM patients was included. A fixed-effect or random-effect model was used for data fitting, heterogeneity was quantitatively evaluated according to the index of I², and sensitivity analysis and publication bias testing were performed by using the standard methods. Results After searching the database through the system, 12 RCTs were included, with a total of 2 276 participants. Due to the potential heterogeneity, a random effect model was used for data fitting. DPP-4i treatment could mildly increase Cr levels in T2DM patients (WMD:0.15 mg/L, 95%CI:0.03～0.27, I²＝18%, P＝0.02), and the results showed statistical differences. According to sensitivity testing, the results of Meta-analysis were relatively reliable. No publication bias was observed according to Begg’s and Egger’s tests. Conclusions The use of DPP-4i for hypoglycemic treatment in T2DM patients may result in mild elevation of blood Cr levels. Further multicenter studies with larger samples are needed in the future to explore the clinical significance of DPP-4i treatment induced changes in Cr levels.