Background: Diabetics with coronavirus disease 2019 (COVID-19) manifest more adverse clinical outcomes with elevated rates of death. It has been suggested that the SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) pathway of entrance into the host cell might be assisted by dipeptidyl peptidase-4 (DPP4), leading to inflammation and cytokine storm, with replication into the airways and unfavorable effects in the lungs. Consequently, the goal of this systematic review is to investigate the most recent data on the effect of DPP-4i (dipeptidyl peptidase-4 inhibitor) medications on clinical outcomes, mainly mortality among COVID-19 patients. Methods: By conducting a systematic search using PubMed and the Cochrane library, observational studies were identified to examine the association between DPP-4i medications and clinical outcomes including mortality, intensive care unit and hospital admissions. The methodologies of included studies were assessed utilizing the Newcastle–Ottawa Scale (NOS). Results: A total of nineteen studies were included with sample sizes varying from over 100 patients to 2.8 million and variant follow-up durations from 30 days up to discharge or death. Most of the population across the studies had COVID-19 for the first time, and the majority were hospitalized. Similarly, mortality definition varied among studies with different time points consisting of 30-day mortality, in-hospital mortality, or all-cause mortality. The majority of the studies identified no effect on mortality by DPP-4i, while a considerable proportion revealed beneficial effects; only four studies showed increased mortality. Conclusions: Real-world data from this review suggested a safe use of DPP-4i among COVID-19 patients; however, randomized clinical trials are required to confirm the beneficial outcomes and safe use.