Abstract: Irisin, a myokine released during exercise, has been shown to exert protective effects against metabolic and inflammatory disorders. Its role in mitigating hepatic damage induced by anabolic-androgenic steroids (AAS) remains largely unexplored. This study was conducted to examine the effects of exercise on irisin level and its capability to prevent hepatotoxicity caused by anabolic androgenic steroids (AAS) in rat model. The fifty-two male rats were divided into four groups: control, AAS treated (15 mg/kg/day S.C/8 W), exercised, and exercised- AAS treated. The following procedures were carried out: liver function tests, serum irisin, tissue inflammatory and oxidative stress markers, macro and micromorphological evaluation, and the examination of nuclear factor erythroid 2-related factor 2 (Nrf2), peroxisome proliferator-activated receptor-gamma (PPARγ) and its coactivator-1α (PGC1α) by immunohistochemistry. The liver tissue’s expression of nuclear factor kappa B (NF-κB), Toll-like receptor-4 (TLR4), and Nrf2 mRNA was also assessed. After administering AAS to animals, aerobic exercise was found to significantly improve liver function tests, inflammation, and oxidative stress, reduce liver weight, improve morphological and histological changes, and improve the hepatic injury score. Furthermore, there was a notable rise in serum irisin, hepatic PPARγ, PGC1α, and Nrf2 immune-expressions and Nrf2 mRNA expression, while NF-κB and TLR4 mRNA expressions were significantly decreased. In conclusion, the irisin/PGC1α/PPARγ/Nrf2 and Nrf2/NF-κB/TLR4 signaling pathways may be modulated by aerobic exercise, which also reduces the liver’s oxidative stress and inflammatory reactions to AAS treatment.