A 2 × 2 × 2 factorial experiment was conducted to investigate the effect of a high level of sorghum distillers dried grains with solubles (DDGS; 20%), with or without a combination of protease and xylanase in broiler chickens, under a necrotic enteritis disease challenge. A total of 576 male broiler chicks were randomly assigned to 8 experimental treatments, each replicated 6 times, with 12 birds per replicate for 35 d. Oral inoculation of the challenged group with Eimeria spp. occurred on d 9, followed by 3 consecutive inoculations of Clostridium perfringens from d 14 through 16. The disease challenge and DDGS inclusion significantly (P < 0.01) interacted, depressing BW gain and feed conversion ratio only in wk 3. Disease challenge adversely influenced (P < 0.01) BW gain and feed conversion ratio of the birds in the third week and across the 35-d study. Over the last 2 wk and across the 35-d trial, the interaction between DDGS and enzyme supplementation showed a tendency (P = 0.09) to gain more BW in birds regardless of the disease challenge. Inclusion of 20% DDGS markedly (P < 0.01) interacted with disease challenge, accelerating the proliferation of C. perfringens in the ceca at d 17. Inoculation of birds with C. perfringens resulted in higher (P < 0.01) counts of C. perfringens in both ileal and cecal contents. The necrotic enteritis-related lesions (d 17) were more severe (P < 0.05) in the intestine of infected birds fed DDGS diets than in birds fed the control diet. Incorporation of DDGS to the diets improved (P < 0.01) the IgA and IgG titer at d 13 but interacted with the disease challenge, reducing the concentration of IgA at d 21 and IgM at d 35 in the infected birds. In conclusion, incorporating a high level of DDGS in the diet of broiler chickens may increase susceptibility to necrotic enteritis. Supplementation of enzymes did not reveal significant mitigation effect in infected birds but helped the birds fed DDGS to maintain feed intake and BW gain.