BACKGROUND: Enterotoxigenic Escherichia coli (ETEC) is one of the primary causes of diarrhea in piglets, creating substantial economic losses in the swine farming industry worldwide. This study aimed to investigate the impacts of zinc caproate (ZnCA, C RESULTS: The addition of 1,600 mg/kg ZnCA to the diet of post-weaning piglets effectively enhanced growth performance and nutrient digestibility and reduced the incidence of diarrhea and inflammatory reactions caused by ETEC K88 infection. These therapeutic effects were comparable to those of pharmacological doses of ZnO. In terms of improving intestinal health and Zn homeostasis in post-weaning piglets challenged with ETEC K88, the effectiveness of 1,600 mg/kg ZnCA surpassed that of pharmacological doses of ZnO. CONCLUSIONS: Overall, under the experimental conditions of this study, ZnCA exhibited the potential to reduce the pharmacological dosage of ZnO while improving intestinal health and Zn homeostasis in weaned piglets.