Emodin, a potential anti-diabetic nephropathy agent, is limited by its oral use due to the poor water solubility. The present study aimed to enhance the absorption and the suppressive effects of emodin on renal fibrosis by developing a self-microemulsifying drug delivery system (SMEDDS). Solubility studies, compatibility tests, pseudo-ternary phase diagrams analysis and central composite design were carried out to obtain the optimized formulation. The average droplet size of emodin-loaded SMEDDS was about 18.31 ± 0.12 nm, and the droplet size and zeta potential remained stable at different dilution ratios of water and different values of pH varying from 1.2 to 7.2. Enhanced cellular uptake in both the Caco-2 cells and glomerular mesangial cells (GMCs) is great advantageous for the formulation. The AUC0–24 h of emodin-loaded SMEDDS was 1.87-fold greater than that of emodin suspension, which may be attributed to enhanced uptake in Caco-2 cells. Moreover, emodin-loaded SMEDDS showed better suppressive effects on the protein level of fibronectin (FN), transforming growth factor-beta 1 (TGF-β1) and intercellular adhesion molecule 1 (ICAM-1) than the crude emodin in advanced glycation-end products (AGEs)-induced GMCs and renal tubular epithelial cells (NRK-52E). Our study illustrated that developed SMEDDS improved the oral absorption of emodin, and attained better suppressive effects on the protein level of renal fibrosis compositions in AGEs-induced GMCs and NRK-52E cells.