Background <p>Metabolic Dysfunction-Associated Fatty Liver Disease (MAFLD) is considered the hepatic aspect of metabolic disorders and is associated with an increased risk of chronic kidney disease (CKD).</p> Aim <p>This study aimed to assess the potential association of Cytokeratin-18 (CK-18) and soluble CD36 (sCD36) biomarkers and the diabetic kidney disease (DKD) in diabetic patients having MAFLD or not.</p> Methods <p>This was a prospective observational study that included adult patients with type 2 diabetes mellitus (T2DM) who were enrolled in three groups as follows: Group A (diabetic patients who had MAFLD) and Group B (diabetic patients with no MAFLD), while Group C included healthy controls. Serum levels of CK-18 and sCD36 were quantified in the three groups.</p> Results <p>Compared with controls, Groups A and B exhibited higher fasting blood glucose (FBG), HbA1c, adverse lipid profiles, and impaired kidney function. Group A demonstrated significantly elevated CK-18 and sCD36 levels versus Group B (<i>p</i> &lt; 0.001). Both biomarkers correlated significantly with anthropometric, metabolic, and renal parameters. In multivariate logistic regression, sCD36 was the sole independent predictor of diabetic nephropathy. ROC analysis showed comparable diagnostic performance of CK-18 (AUC 0.896) and sCD36 (AUC 0.901) for predicting nephropathy.</p> Conclusion <p>CK-18 and sCD36 are promising noninvasive biomarkers for the early depiction of kidney involvement in MAFLD diabetic patients.</p>