Diabetes mellitus (DM) is a pandemic metabolic disease characterized by a chronicallyelevated blood glucose concentration (hyperglycemia) due to insulin dysfunction. Approximately 50% of diabeticsshow diabetes complications by the time they are diagnosed. Vascular dysfunction, nephropathy and neuropathicpain are common diabetes complications. Chronic hyperglycemia contributes to reactive oxygen species (ROS)generation such as methylglyoxal (MGO).Methods: Peer reviewed research papers were studied through bibliographic databases searching focused on reviewquestions and inclusion/exclusion criteria. The reviewed papers were appraised according to the searching focus.The characteristics of screened papers were described, and a deductive qualitative content analysis methodologywas applied to the included studies using a conceptual framework to yield this comprehensive systematic review.Results: Sixty-six papers were included in this review. Eleven papers related methylglyoxal generation to carbohydrates metabolism, tenpapers related lipid metabolism to methylglyoxal and 5 papers showed the proteolytic pathways that contribute to methylglyoxal generation.Methylglyoxal metabolism was derived from 7 papers. Descriptive figure 1 was drawn to explain methylglyoxal sources and howdiabetes increases methylglyoxal generation. Furthermore, twenty-six papers related methylglyoxal to diabetes complications from which9 papers showed methylglyoxal ability to induce insulin dysfunction, an effect which was described in schematic figure 2. Additionally,fifteen papers revealed methylglyoxal contribution to vascular dysfunction and 3 papers showed methylglyoxal to cause neuropathic pain.Methylglyoxal-induced vascular dysfunction was drawn in a comprehensive figure 3. This review correlated methylglyoxal with diabetesand diabetes complications which were summarised in table 1.Conclusion: The findings of this review suggesting methylglyoxal as an essential therapeutic target for managing diabetes in the future.