Reactive oxygen species (ROS)-mediated apoptosis of intestinal epithelial cells and loss of tight junction (TJ) proteins may be the primary causes of mycophenolic acid (MPA)-induced disruption of intestinal epithelial barrier function, leading to intestinal toxicity. Currently, there are no effective preventive or curative drugs for this condition. Schisanhenol (Sal), the most potent antioxidant lignan component in the traditional Chinese medicine Schisandra chinensis. The aim of this study was to examine the protective effects and potential mechanisms of Sal on MPA-induced damage to the intestinal mechanical barrier. After co-treating Caco-2 cells with Sal and MPA for 24 hours, we observed that Sal significantly reversed MPA-induced inhibition of cell viability, increased Bcl-2 protein expression, and reduced apoptosis. Sal also significantly upregulated the expression of TJ proteins ZO-1 and occludin, thereby reducing paracellular gaps. Additionally, the nuclear factor-E2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) pathway, which is crucial in regulating cellular redox homeostasis. Results showed that Sal inhibited MPA-induced activation of the Nrf2/HO-1 pathway, decreased ROS production, and increased antioxidant levels. In conclusion, Schisanhenol may exert a protective effect against MPA-induced damage to the intestinal epithelial barrier by activating the Nrf2/HO-1 pathway and improving cellular antioxidant capacity.