Azathioprine (AZA) is a widely employed immunosuppressive and chemotherapeutic medication that may exhibit detrimental effects on testes. Fluvastatin is a lipid-lowering agent with promising reproductive properties. This work aimed to assess the testicular toxicity of AZA and the probable protective role of fluvastatin. Forty adult male albino rats were assigned to four equal groups: Control, Fluvastatin (6 mg/kg), AZA (15 mg/kg), and AZA and fluvastatin. After 4 weeks, sera were obtained for testosterone, luteinizing hormone (LH), and follicle stimulating hormone (FSH) investigations. Semen samples were collected to test sperm parameters. Testes were harvested for biochemical investigations, gene transcription, and histological and immunohistochemical examinations. In the AZA group, results exposed a considerable decline in sperm parameters, sex hormones, and testicular weight. Oxidative stress was evident by the diminished catalase (CAT) and superoxide dismutase (SOD) activity, and malondialdehyde (MDA) levels elevation. Inflammation was reflected by increased NOD-Like Receptor family, Pyrin domain-containing 3 inflammasome (NLRP3), Interleukin-6 (IL-6), and Interleukin-1 Beta (IL-1β), besides decreased Interleukin-10 (IL-10). Gene transcription indicated that AZA disrupts the mammalian target of the rapamycin (mTOR) cascade and the autophagic and apoptotic-related genes in testes, thus impairing the blood-testis barrier (BTB) and spermatogenesis. Testes displayed disorganized germinal epithelium and deformed seminiferous tubules. A positive p53 immunoreaction and a lost vimentin spoke-like pattern were also demonstrated. Fluvastatin exhibited antioxidant and anti-inflammatory defense, regulated the mTOR pathway, restored the lost autophagy/apoptosis balance, and improved the architectural and immunohistochemical alterations.