Introduction: Diabetes mellitus induces atrophy in splenic lymphoid follicles, which may affect the body defense mechanisms. Mesenchymal stem cells could be a practical approach to treat diabetes-induced spleen damage. Aim of work: To demonstrate the histological changes in adult albino rat's spleen after induction of diabetes and to assess the effect of injected mesenchymal stem cells (MSCs) treated with L-carnitine on alleviating these changes. Materials and Methods: Thirty adult male albino rats were divided into 3 main groups: Group I (control), Group II (diabetic): the rats were injected once with intra-peritoneal Streptozotocin (STZ) 50mg/kg and group III (Diabetic +MSCs): the animals were injected intravenously with MSCs four weeks after diabetes confirmation. All rats were sacrificed four weeks after MSC injections (8 weeks from the beginning of the experiment) and spleen specimens were processed to be examined by light microscope. Blood specimens were collected to measure glucose and insulin levels. The mRNA expression for Nrf2, IL 10 and IL 17A was measured by Real-time Polymerase Chain Reaction (RT-PCR). Results: Degenerative changes were observed in diabetic group in the form of reduced size of white pulp with many apoptotic nuclei. Widened congested red pulp, statistical significant reduction of insulin level, white pulp volume, area percent of CD4+ and nuclear factor erythroid 2 related factor 2 (Nrf2) immunoexpression and also in qRT-PCR relative gene expression of Nrf2 and IL 10. There was significant increase in blood glucose level and qRT-PCR relative gene expression of IL 17A. All changes were reversed in MSCs treated group. Conclusion: We concluded that L-carnitine pretreatment of MSCs releases a novel way to enhance MSCs therapeutic potential efficacy in spleen of experimental diabetic rats with recommendation of trying further researches for their application in other vital organs.