Cathelicidins are the largest family of antimicrobial peptides. C-BF, which is short for Cathelicidin-Bungarus Fasciatus, was isolated from snake venom. C-BF was found to be the most potential substitutes for antibiotics. In this study, we analyzed the effects of cathelicidin-derived peptide C-BF, on lipopolysaccharide (LPS)-induced intestinal damage in weaned piglets, to evaluate the therapeutic effect of C-BF on infectious disease of piglets. Twenty-four piglets were randomly assigned into four groups: control, C-BF, LPS, and C-BF+LPS. The LPS and C-BF+LPS groups were intraperitoneally injected with LPS at fixed timepoints, while the control and C-BF groups were injected with equal volumes of saline. The C-BF and C-BF+LPS groups were then intraperitoneally injected with antimicrobial peptide C-BF, while the control and LPS groups were injected with equal volumes of saline. All piglets were observed for 15days and then sacrificed for analysis. The results showed that C-BF significantly improved the growth performance of weaned piglets compared with LPS-treated animals (P<0.05), and that C-BF could ameliorate the structural and developmental damage to the small intestine caused by LPS treatment. Further, the level of apoptosis in the LPS group was significantly higher than in the other three groups (P<0.05), as was the invasion of inflammatory cells into the intestinal mucosa of the jejunum (P<0.05), leading to increased secretion of pro-inflammatory cytokines. In conclusion, the study indicates that C-BF treatment may be a potential therapy for LPS/pathogen-induced intestinal injury in piglets.