BACKGROUND: DM is a common chronic metabolic disease. COVID-19 is a large-scale infectious disease. Some studies have shown that DM is an independent risk factor that increases COVID-19 mortality or other adverse outcomes. There is currently no specific and effective drug treatment. More and more people realize that DPP-4 inhibitors may play a huge role in fighting COVID-19 combined with diabetes. However, there is no evidence-based medicine to confirm the effectiveness and safety of DPP-4 inhibitors in the treatment of COVID-19 patients with diabetes. Therefore, we will conduct a systematic review and meta-analysis to synthesize the existing clinical evidence. METHODS AND ANALYSIS: Electronic databases include CNKI, Wanfang, VIP, CBM database, Cochrane Library, PubMed, Web of Science, EMBASE, etc. We will retrieve each database from December 2019 to September 2020. At the same time, we will look for clinical trial registration and gray literature. This study only included clinical randomized controlled trials. The reviewers independently conduct literature selection, data analysis, quality analysis, and evaluation. The primary outcomes include mortality rate, morbidity, interleukin-6, tumor necrosis factor-alpha, clinical improvement, symptoms improvement, fasting blood glucose, 2-hour postprandial blood glucose, glycosylated hemoglobin, fasting insulin, adverse reactions, etc. Finally, we will conducted a meta-analysis through Review Manager Software version 5.3. RESULTS: The results will be published in peer-reviewed journals and presented at a relevant conference. CONCLUSION: This study will explore the effectiveness and safety of DPP-4 inhibitors in the treatment of COVID-19 patients with diabetes. It will provide evidence-based medical evidence for DPP-4 inhibitors in the treatment of diabetes with COVID-19. REGISTRATION NUMBER: INPLASY202090015.