Moringa Oleifera (MO) is a herbal plant native to South Asia known for its anti-oxidative and anti-inflammatory properties. This study explored the protective effects of MO leaf extract (MOLE) against oxidative stress and hepatic and renal injuries caused by methotrexate (MTX) therapy. Mice received a single intraperitoneal injection of 20 mg/kg body weight MTX to induce hepatic and kidney injuries. They then received 300 mg/kg body weight of MOLE orally for seven days, followed by MTX on day 7 then five more days of MOLE (12 days total). Blood, liver and kidney samples were collected from all groups and the following biochemical parameters were tested: serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), catalase, superoxide dismutase (SOD), malondialdehyde (MDA) and total proteins. Quantitative real time PCR (qRT-PCR) was used to examine Nrf2, HO-1, BAX, TIMP, XIAP, and NFkB, which are associated with apoptosis, anti-apoptosis and oxidative stress. Capase-9 and Bcl2 genes underwent immunohistochemical analysis. Pretreatment with MOLE reduced the effect of MTX on ALT, AST and total proteins, and reversed its effect on serum and tissue antioxidants. Nrf2/HO-1, apoptotic and anti-apoptotic gene expression was regulated, and Bax and TIMP were reduced; XIAP expression was increased in both the liver and kidney samples, and immunoreactivity of caspase-9 and Bcl2 was restored in the MOLE-administered experimental group. Overall, the study concluded that MOLE can inhibit the effects of hepato-renal injuries caused by MTX by regulating oxidative stress, apoptosis and anti-apoptotic genes at biochemical, molecular and cellular levels.