Background: The aim of the present study was to systematically review the efficacy and safety of mecobalamin combined with prokinetic agents in diabetic gastroparesis (DGP). Methods: A variety of databases were searched from inception to Nov 2, 2018. RCTs of mecobalamin combined with prokinetic agents group (experimental group) versus prokinetic agents only group (control group) in DGP were included. RevMan 5.3 and Stata 12.0 were used to perform the meta-analysis. Finally, 24 RCTs with 1,878 patients were included. Results: The total efficacy rate was significantly higher in the experimental group (mecobalamin combined with prokinetic drugs) compared with the control group (prokinetic drugs alone) (P<0.001), and the improvement was observed regardless of the administration route. Furthermore, the treatment group exhibited a significantly improved gastric emption rate (P<0.001), motilin (P<0.001) and recurrence rate (P<0.001), and there was no statistical difference in the incidence of adverse reactions between two groups (P=0.49). Conclusion: Mecobalamin combined with prokinetic agents can significantly improve total efficacy rate and gastric emptying rate, decrease serum motilin and the recurrence rate without increasing adverse reactions in DGP. Thus, mecobalamin may can be used as a new therapeutic option for DGP.