Trichinella spiralis and porcine epidemic diarrhea virus (PEDV) are two infectious swine pathogens. Parasite excretory/secretory antigens play critical roles in various disease processes. To explore the coexistence mechanism of two pathogens infecting the same host, the intestinal organoid was utilized to reproduce these biological processes. In this study, we investigated the effects of T. spiralis excretory/secretory antigens (TsES) on PEDV-induced inflammatory regulation, lesion recovery, and mucosal barrier repair in porcine intestinal organoids. The results showed that PEDV effectively infected the porcine intestinal organoids. Next, TsES inhibited pro-inflammatory cytokines and increased the anti-inflammatory cytokines produced by PEDV-infected porcine intestinal organoids. Further, four-dimensional (4D) label-free quantitative proteomics and western blotting confirmed that TsES regulate the inflammation caused by PEDV infection through the nuclear factor kappa-B (NF-κB) pathway. In addition, TsES promoted cell proliferation, inhibited apoptosis, and reduced PEDV-induced lesions in intestinal organoids. The elevated secretory immunoglobulin A (sIgA) levels caused by PEDV infection were downregulated by TsES treatment in intestinal organoids. TsES treatment reversed the mucosal barrier damage caused by PEDV infection in intestinal organoids. Finally, PEDV replication increased after TsES treatment in organoids. We highlight the potential of TsES to ameliorate PEDV-induced inflammation, mucosal lesions, and barrier damage in porcine intestinal organoids. TsES also contribute to PEDV replication. This study presents a novel research model for research on host-virus-parasite interactions, while also providing a theoretical foundation to consider parasite derivatives as a potential adjunctive therapy for intestinal inflammation.