Background: Diabetic nephropathy (DN) is a leading cause of chronic kidney disease and end-stage renal disease worldwide. The maternally expressed gene-3 (Meg3), a lncRNA, is implicated in the development of diabetic microvascular complications like retinopathy and nephropathy. MicroRNA-21 (miRNA-21) and Transforming Growth Factor-Beta (TGF-β) are established playmakers in fibrogenesis in DN. Research stated that MEG3 can sponge miRNA-21 inhibiting it. Additionally, MEG3modulates the activity of TGF-β genes by binding to promotor-distal regulatory elements. Aim: Investigate MEG3 regulatory role in DN pathogenesis, and its possible inhibitory effect on miRNA-21 and TGF-β signaling pathways. Methods: The study was performed on 75 subjects divided into 3 groups: 25 controls, 25 diabetics, and 25 DN patients. Participants were subjected to routine laboratory investigations, estimation of gene expression of MEG3 and miRNA-21 by RT-qPCR and measurement of serum TGF-β levels by ELISA. Results: DN group shows a highly significant decrease in MEG-3 relative gene expression, and a significant increase in both miRNA-21 relative gene expression and TGF-β sera levels, when compared to diabetic and control groups. In addition, MEG3 is significantly negatively correlated to miRNA-21, TGF-β1, and HbA1c confirming the sponging effect of MEG3 on miRNA-21 and predicting its potential protective role in DN. On the other hand, there is a statistically significant positive correlation between miRNA-21 gene expression and TGF-β1 levels indicating the up-regulatory role of miRNA-21 on TGF-β1 protein expression levels. Conclusion: Our data suggest that MEG3 is implicated in DN pathogenesis through a possible loop encompassing miRNA-21 and TGF- β1.