Background: Fibroblast growth factor 21 (FGF21) is a hepatokine involved in the glucose and lipid metabolism that increases in cases of metabolic stress. Hyperglycemia and insulin resistance can increase FGF21, potentially leading to FGF21 resistance. Interestingly we aimed to evaluate serum FGF21 levels across prediabetes, type 2 diabetes mellitus, and healthy controls, and to examine their associations with microvascular complications. Methods: This case-control study involved 42 participants divided equally into three groups (n= 12 in each): control, prediabetes, and T2DM. We evaluated anthropometric indices and biochemical parameters fasting glucose, Glycated hemoglobin (HbA1c), lipid profile, creatinine, and FGF21. Results: Serum FGF21 levels increased significantly across groups (p < 0.001), being highest in diabetes (≈932 pg/mL), intermediate in prediabetes (≈532 pg/mL), and lowest in controls (≈239 pg/mL). Body mass index, fasting glucose, and HbA1c were significantly higher in prediabetic and diabetic subjects versus controls (all p < 0.001). HDL cholesterol was significantly lower, whereas total cholesterol and triglycerides were higher in both groups (p < 0.001 and p = 0.024). However among diabetic patients, neuropathy (71.4%) and retinopathy (42.8%) were associated with higher FGF21 levels (p = 0.005 and p = 0.010, respectively). FGF21 showed positive correlations with HbA1c (r = 0.42, p = 0.021), LDL cholesterol (r = 0.28, p = 0.040), creatinine (r = 0.32, p = 0.026), as well as BMI (r = 0.37, p = 0.023). ROC analysis showed strong diagnostic accuracy for identifying prediabetes (AUC = 0.90) and diabetes (AUC = 0.95) (both p< 0.001). Conclusion: Serum FGF21 levels increased progressively from normal glucose tolerance to prediabetes and highest in type 2 diabetes mellitus. Diabetic patients who had neuropathy or retinopathy showed significantly higher levels. The strong diagnostic accuracy of FGF21 supports its being as an early biomarker for metabolic dysfunction and microvascular complications among diabetic patients.