Background: Beside its hematopoietic functions, erythropoietin (EPO) exhibits non- hematopoietic functions. EPO has anti-apoptotic, anti-oxidant and anti-inflammatory activities. Tissue-protective effect of EPO was confirmed in brain, myocardium, kidney and liver injury. Mesenchymal Stem Cells (MSCs), with its remarkable capacity of self renewal and differentiation, provide opportunities for treating many diseases including acute liver failure. Experimentally, acute liver injury can be induced by well-known and often used hepatotoxin, galactosamine (GalN). Aim of work: Investigating the possible protective effect of both EPO and MSCs on GalN-induced liver injury and trying to clarify their mechanism of action. Methods: In vitro study: isolated bone marrow-MSCs were treated by EPO and cell proliferation and gene expression of Caspase-3, BAX/BCL-2 ratio and STAT-5 were assessed. In vivo study: One hundred, male adult white albino rats were divided into five groups each consists of 20 rats. IL-6, IL-10 levels and NFκb, iNOS, TLR4&BAX gene expressions were assessed in liver tissue. ALT, AST, albumin and ammonia levels were assessed in serum. Histopathology and immunohistochemical study of COX-2 were done. Results: EPO and MSCs treatment corrected the toxic effect of GalN with significant increase in the mean level of IL-10 & albumin and significant decrease in the mean level of IL-6, (NFκb, iNOS, TLR4& BAX gene expression) and (ammonia, ALT& AST). The combination between MSCs and EPO enquired more protection against GalN toxicity. EPO significantly decreased (BAX/BCL-2 ratio & caspase-3 gene expression) and significantly increased (proliferation of MSCs & STAT-5 gene expression). Conclusion: MSCs and EPO as separate or combined therapy protect liver against GalN toxicity may be through immunomodulation and anti-apoptotic activities.