Background: One of the most severe consequences of diabetes mellitus and end-stage renal failure is diabetic nephropathy (DN), which is regarded as such globally. Exosomes, which are released by a variety of cells, are one of the cutting-edge, hopeful treatments for chronic kidney damage. Objective: This study assessed the effects of exosomes made from mesenchymal stem cells and an aqueous extract of the fruit of the Balanites aegyptiacae plant on DN in a diabetic rat model. It was suggested that balanites and exosomes could regulate diabetic kidney problems and function as a potential novel regulator in DN therapy. Methods: Seven groups of 70 mature male albino rats, weighing 180–200 g, were created: Groups I and II are the negative control groups, Group III is the Balanites-treated group, Group IV is the MSCs-treated group, Group V is the Exosome- treated group, Group VI is the Balanites + MSCs-treated group, and Group VII is the Balanites + exosome- treated group. The following measurements were made: plasma glucose, serum insulin, total cholesterol, triacylglycerol, and a kidney function test. Also performed was a histopathological evaluation of pancreatic tissue. Results: Balanites aegyptiacae co-administration with MSCs or exosomes showed a significant reduction in the concentrations of plasma glucose, total cholesterol, triacylglycerol, urea and creatinine. Furthermore, there was a significant rise in insulin levels in the groups co-administered Balanites aegyptiacae with MSCs or exosome as well as, enhanced regeneration of beta cell of the pancreas. Conclusion: These results clearly revealed that Balanites aegyptiacae co-administration with exosome has synergistic effect for each other and gives a higher renoprotective effect in rats with DN. In addition, Balanites aegyptiacae fruit aqueous extract exhibited potential anti-hyperglycemic and antihyperlipidemic effects.