BACKGROUND: The adverse effects of radiotherapy (RT) primarily occur through oxidative stress, and attempts are being made to mitigate these effects. L-Carnitine (L-Car) involved in physiological functions, possesses antioxidant and tissue-protective properties. The goal of this investigation is to appraise the radioprotective efficacy of L-Car supplementation. METHODS AND RESULTS: The groups were established by dividing thirty-two rats as: control, RT (10 Gy), RT + L-Car (200 mg/kg/d), L-Car. Upon completion of the experiment, the livers were harvested for histopathological, immunostaining [tumor necrosis factor-alpha (TNF-α), Caspase-3], spectrophotometric [total oxidant status (TOS), total antioxidant status (TAS), oxidative stress index (OSI)], and mRNA expression [(Nuclear factor erythroid 2-related factor 2 (Nrf2), Kelch-like ECH-associated protein 1 (Keap-1), Heme Oxygenase (HO-1), Transforming growth factor beta 1 (TGF-β1)] analyses. In the damage group, decreased Keap-1, Nrf2, HO-1, and TAS values, along with increased histopathological findings, alanine transferase, aspartate transferase, TNF-α, Caspase-3, TOS, OSI, TGF-β1 levels were found. All findings were improved with L-Car treatment. CONCLUSIONS: Considering these findings, it can be inferred that L-Car exhibits tissue-protective effects against organ damage predominantly induced by RT-related oxidative stress. Additionally, it has prevented the development of inflammation, apoptosis, and fibrosis. Therefore, L-Car may be considered as a supplement to reduce complications associated with RT.