Leishmania major is a protozoan parasite that causes cutaneous Leishmaniasis disease in human beings and animals. The disease is prevalent in tropical and semitropical countries and has great health importance. The present study aimed to identify the histological changes in the organs infected with L. major and to provide a sophisticated diagnostic method for infection through detecting TGF-β cytokine by immunohistochemistry technique(IHC) from October 2020 to January 2021. A total of 40 samples of paraffin blocks were used for different organs including skin, spleen, liver, kidney, and heart of male and female BALB/c mice, aged 6-8 weeks, which were previously infected subcutaneously with L. major promastigotes at a dose of 1×107 promastigotes/moues. The result indicated epidermal hyperplasia with diffuse severe lymphohistiocytic inflammatory cells infiltration in the dermis. Hyperplasia of the lymphoid follicles was observed in infected spleen and scattered polymorphonuclear cells mainly neutrophil masses with a random distribution of microgranulomas foci composed of lymphocytes and macrophages within the liver parenchyma around central veins and portal areas. The infected kidney showed aggregation of perivascular mononuclear cells (lymphocytes and macrophages) in the renal cortex. Mononuclear lymphocytes and macrophages were observed within the heart parenchyma especially around blood vessels. Additionally, evaluation of TGF-β1 expression was highly strong for skin, spleen, relatively strong for liver, heart, and weak for the kidney. In conclusion, infection was accompanied by clinical and histological changes as well as inflammatory diseases. Furthermore, the determination of TGF-β expression level depends on the diagnosis of infection. A clear understanding of immune mechanisms is essential for preventing, treating, and controlling strategies of this infection.