The present study aimed to determine the hepatoprotective effect of different extracts of Olea europaea L. seeds in mice induced with MTX-induced liver injury and find the most effective extract. Olea europaea L. (olive) seeds powder was extracted with three solvents with different polarities in a sequential manner (chloroform, methanol, and 50% aqueous ethanol) using the cold method. 48 male albino mice were divided into six groups. Mice were pretreated orally with silymarin (standard) and the test extracts for 5 consecutive days at a dose of 200mg/kg and 500mg/kg consecutively. Mice received methotrexate (20mg/kg) IP single dose on day 5. On day 6, blood samples were collected for biochemical analysis of serum liver indices; then animals were sacrificed to collect liver tissues for histological examination. The antioxidant activity for each extract was assessed using the DPPH assay. The results indicated that MTX successfully induced liver damage that was observed through marked elevation of serum GPT, GOT, and ALP as well as alterations in the cellular structure of liver tissue. All extracts of olive seeds were able to reduce serum levels of liver indices. However, 50% ethanol extract was revealed to be the best in reducing levels of GPT, GOT, and ALP, preserving liver tissue cellular structure, and having the highest free radical scavenging activity in DPPH assay. The study suggests that 50% ethanol extract of Olea Europaea L. seeds can be safely used with MTX therapy to reduce its hepatic toxic effect.