Methotrexate (MTX) is commonly used to treat individuals with rheumatological and dermatologic disorders. Current American College of Rheumatology (ACR) and American Association of Dermatology (AAD) guidelines identify diabetes and obesity as risk factors for MTX-induced liver injury. Both diabetes and obesity are components of the metabolic syndrome, and are also risk factors for nonalcoholic fatty liver disease (NAFLD). NAFLD affects approximately 40% of the U.S. population, and those with more advanced NAFLD (i.e., nonalcoholic steatohepatitis with or without fibrosis) are likely to develop progressive liver disease. As such, individuals who are treated with MTX may need to be screened for advanced NAFLD, as this may put them at an increased risk of MTX-induced liver injury. In this mini-review, we review the current ACR and AAD guidelines on MTX hepatotoxicity, discuss the evidence (or lack thereof) of the impact of metabolic risk factors on MTX-induced liver injury and highlight the areas that need further research.