The objective of this study was to investigate the effects of cathelicidin-BF (C-BF) derived from the Chinese endemic genera Bungarus fascia on postweaning diarrhea, growth performance, intestinal morphology and inflammation in weanling piglets. Eighteen piglets (Duroc × Landrace × Yorkshire) were weaned at 21 d with an initial BW of 6.63 ± 0.13 kg and randomly assigned to one of 2 treatments to give 3 pens per treatment and 3 piglets per pen. Piglets were intraperitoneally injected with normal saline (control group) or 0.55 mg/kg BW C-BF (C-BF group) once a day and offered diets and water on an ad libitum basis for 7 d. Diarrheal index was scored twice daily according a 4-point system (0, normal; 1, soft feces; 2, mild diarrhea; and 3, severe diarrhea). The ADG, ADFI and G:F were calculated at the end of study. All piglets were euthanized to determine serum immunoglobulin, serum cytokines, intestinal morphology and intestinal inflammation. Our data showed that C-BF treatment increased ADFI (245.4 vs. 157.9 g/d, P < 0.05) and ADG (181.9 vs. 112.9 g/d, P < 0.05) compared with control group. Meanwhile, C-BF treatment reduced diarrheal index compared with control (0.47 vs. 1.67, P < 0.05). Serum IgG, IL-6, IL-22 and TNF-α production were decreased (P < 0.05) by C-BF treatment. C-BF increased (P < 0.05) villus height of jejunum and reduced (P < 0.05) crypt depth of ileum. We demonstrated that C-BF reduced (P < 0.05) the expression of the inflammatory cytokines TNF-α, IL-6 and IL-8, but increased the expression of the anti-inflammatory cytokine IL-10 (P < 0.05) in the jejunum. Furthermore, we demonstrated that C-BF suppressed inflammation by downregulating the nuclear factor-κB (NF-κB) signaling pathway in the jejunum. In summary, these data suggest that intraperitoneal injections of C-BF ameliorated postweaning diarrhea and improved growth performance along with suppressing intestinal inflammation by downregulating the NF-κB signaling pathway in weanling piglets.