Hepatotoxicity is the main secondary effect caused by methotrexate, it is the drug widely used to treat autoimmune diseases, malignant tumors, cancer, psoriasis, rheumatoid arthritis (RA), lupus, ectopic pregnancy, leukemia, and other ailments. In recent years, in vivo and in vitro research has been carried out focused on the search for hepatoprotective agents that help reduce the damage caused by this drug. This work aims to describe the hepatoprotector effect of natural bioactive compounds (carvacrol, phloridzin, berberine, pentoxifylline, chlorogenic acid, gallic acid, resveratrol, rutin, quercetin, thymoquinone, lycopene, alpha lipoic acid, ozone and melatonin), isolated from medicinal plants as well as from organic extracts of medicinal plants such as Curcuma longa, Sphaeralcea angustifolia, Balanites aegyptica, Morus nigra, Spinacea oleracea, mixture from four medicinal plants (Boerhaavia diffusa, Cratoera nurvala, Nelumbo nucifera and Rheum emodi) and pollen) that prevent and/or protect the liver from damage caused by methotrexate. The majority of these evaluations have been performed in in vivo models.