Background: Methotrexate is a stable derivative of aminopterin, a folate antimetabolite. Despite the widespread use of methotrexate, the clinical application of methotrexate is limited and restricted by the occurrence of hepatotoxicity. An important medicinal plant, Capparis decidua contains multiple pharmacological activities such as antioxidant, antiapoptotic, and anti-inflammatory effects. Objectives: This study investigated the protective effect of C. decidua against methotrexate-induced hepatotoxicity, focusing on its ability to attenuate oxidative stress and inflammatory nuclear factor-kappa B (NF-κB) signaling pathway which have not been studied earlier. Materials and Methods: Thirty-six female Wistar rats were randomly divided into six experimental groups. Rats were treated with C. decidua orally with doses of 250 mg/kg and 500 mg/kg for 14 consecutive days following a single dose of MTX injection (20 mg/kg, i. p). Serum levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP) were assessed. Malondialdehyde (MDA) levels, superoxide dismutase (SOD), and catalase (CAT) were assessed in hepatic tissue. mRNA expression of, NF-κB, tumor necrosis factor-alpha (TNF α), interleukin-1beta (IL-1 β), and IL 6 was carried using real-time polymerase chain reaction in hepatic tissue. Results: Results showed that methotrexate administration significantly increased AST, ALT, and ALP levels. It has also increased MDA levels indicating lipid peroxidation and decreased antioxidants levels of SOD and CAT levels. Treatment with C. decidua significantly diminished the hepatotoxic effects of methotrexate which was seen in a significant decrease in AST, ALT, ALP, MDA levels, significant increase in SOD and CAT levels. Methotrexate provoked hepatic NF-κB phosphorylation and increased mRNA abundance of TNF-α, IL-1 β, and IL-6 expression. Conclusion: These findings suggest that C. decidua prevents methotrexate hepatotoxicity through suppression of NF-κB signaling pathway, attenuating oxidative damage, inflammation, and cell death.