Deoxynivalenol (DON) is a prevalent mycotoxin in animal feed that particularly impacts weaned piglets, causing liver damage, growth retardation, and posing significant public health risks. However, the precise mechanisms underlying DON-induced liver damage and optimal treatment approaches remain unclear. The pregnane X receptor (PXR) holds a pivotal position in hepatic xenobiotic elimination and drug metabolism. This research aimed to explore the involvement of PXR in DON-induced liver injury and evaluate the potential of the PXR agonist, 3-indolepropionic acid (IPA), to alleviate liver damage and associated diarrhea in weaned piglets under practical farming conditions. The results demonstrated that DON initiates p53-mediated hepatocyte apoptosis in weaned piglets. RNA-seq and hepatocyte-specific PXR knockout (PXR-HKO) mice revealed PXR's regulatory role in DON-induced hepatocyte apoptosis. IPA reduces DON-induced hepatocyte apoptosis in piglets, mice, and hepatocyte cell lines by enhancing PXR expression and facilitating nuclear translocation. Furthermore, AlphaFold3 predictions and Co-IP assays demonstrate that DON diminishes PXR-p53 binding, thereby amplifying p53-mediated apoptotic transactivation. In conclusion, this study elucidates a novel mechanism by which PXR decreases its binding to p53 upon DON exposure, thereby promoting hepatocyte apoptosis. Additionally, it validates the positive impact of IPA in mitigating liver damage and diarrhea caused by DON in weaned piglets.