Background: The hippocampus is a major component of the mammalian brains and the brains of other vertebrates. It belongs to the limbic system and plays important roles in memory consolidation. Methotrexate (MTX) belongs to the antimetabolite group, which is an antineoplastic group of drugs. MTX has a wide range of therapeutic effects: e.g. at high doses in many malignancies and at low doses in autoimmune diseases such as rheumatoid arthritis and psoriasis, due to its anti-inflammatory and immunosuppressive effects. The therapeutic actions of Alpha Lipoic Acid (ALA) is based on its antioxidant properties including its capacity in regenerating endogenous antioxidants, its metal chelating abilities, its action as a scavenger of reactive oxygen species (ROS) and its capability to repair oxidative damage. Objective: This work aimed to study the neurotoxic effects of methotrxate (MTX) on rat hippocampus and to explore the neuroprotective role of alpha lipoic acid (ALA). Methods: The databases were searched for articles published in English in 4 data bases [PubMed – Google scholar- Science direct and Egyptian bank of knowledge] and Boolean operators (and, or, not) had been used such as neurotoxic effects of methotrxate and rat hippocampus OR alpha lipoic acid and in reviewed articles. Conclusion: So, from this review article, it can be concluded that, alpha lipoic acid administration along with methotrxate therapy can ameliorate the harmfull effects of methotrxate on hippocampus.