The mycotoxin deoxynivalenol (DON) is a food contaminant that leads to reduced feed intake and reduced BW gain, as well as organ impairment. On the other hand, antimicrobial peptides have been shown to have positive effects on growth performance, nutrient digestibility, and immune function. The purpose of this study was to investigate the protective effects of composite antimicrobial peptides (CAP) on piglets challenged with DON. After a 7-d adaptation period, 28 individually housed piglets (Duroc × Landrace × Large Yorkshire) weaned at 28 d of age were randomly assigned to receive 1 of 4 treatments (7 pigs/treatment): negative control, basal diet (NC), basal diet + 0.4% CAP (CAP), basal diet + 4 mg/kg DON (DON), and basal diet + 4 ppm DON + 0.4% CAP (DON + CAP). On d 15 and 30 after the initiation of treatment, blood samples were collected for the determination of blood profile. Piglets were monitored for 30 d to assess performance and then were slaughtered to obtain organs for the determination of the relative weight of organs. The results showed that dietary supplementation with DON decreased (P < 0.05) ADFI, ADG, and G:F, whereas dietary supplementation with CAP improved ADG and G:F (P < 0.05). The relative weight of the kidney and pancreas was greater and the relative weight of the spleen was lighter in the DON treatment than in the other 3 treatments (P < 0.05). There were no effects (P > 0.05) on other relative weights of viscera, except the relative weight of the gallbladder, but the diamine oxidase activity in the liver decreased in DON-treated piglets (P < 0.05). Piglets in the DON treatment had increased serum concentrations of alkaline phosphatase, alanine transaminase, and aspartate aminotransferase and a dramatic decrease in total protein (P < 0.05), whereas there were no differences (P > 0.05) between the DON + CAP treatment and the other treatments. The DON treatment decreased the numbers of red blood cells and platelets, as well as the serum catalase concentrations, and decreased the serum concentrations of H2O2, maleic dialdehyde, and nitric oxide (P < 0.05). The numbers of platelets and thrombocytocrit, as well as the serum concentrations of catalase, were greater, whereas the maleic dialdehyde concentrations were decreased, in both the CAP and DON + CAP treatments compared with the other treatments (P < 0.05). Compared with the control treatment, DON decreased peripheral lymphocyte proliferation on d 15, whereas supplementation with CAP increased it on d 15 and 30 (P < 0.05). These findings indicate that CAP could improve feed efficiency, immune function, and antioxidation capacity and alleviate organ damage, and thus, it has a protective effect in piglets challenged with DON.