Fusarium mycotoxins are nature environmental contaminants worldwide in animal feed and human food resulting in a serious health risk. The present study aimed to evaluate the potential role of organo-modified nano-montmorillonite (OMNM) against the health risk and the oxidative stress resulted from the exposure of fumonisin (FB) and zearalenone (ZEN) individually and in combination in rats. Eight groups of female Sprague Dawley rats were treated orally for 3 weeks including the control group, FB alone-treated group (50 mg/kg b.w.), ZEN alone-treated group (40 μg/kg b.w), FB plus ZEN-treated group, the group fed basal diet supplemented with OMNM (5 g/kg diet), and the groups fed basal diet supplemented with OMNM and treated with FB and/or ZEN. At the end of the experimental period, samples of blood and tissues were collected for different biochemical and histological analyses. The results revealed that administration of FB and/or ZEN resulted in significant disturbances in the biochemical parameters tested, lipid profiles, serum cytokines, oxidative stress indices, the activity of antioxidant enzymes, and the histological status of the liver and kidney. Co-administration of both mycotoxins indicated a synergistic effect. OMNM alone was safe and succeeded to reduce and/or prevent most of the toxicity of both mycotoxins. It could be concluded that OMNM is a novel and promising nanograde adsorbent suitable for the protection against the combined exposure to FB and ZEN.