This study evaluated the effect of an enzyme blend (xylanase, amylase and protease; XAP) in combination with a direct fed microbial (DFM) containing three strains of Bacillus spp. on intestinal histology, immune response and performance of broilers. Four dietary treatments were tested in a 2 × 2 factorial trial, including two levels of challenge (without or with coccidial infection), two levels of feed additive (with or without XAP and DFM). Diets were fed ad libitum to male Cobb500 broilers in mash feeds from 1–21 days of age, with eight replicate pens per treatment within brooder-batteries with raised wire floors and built up litter, housing six birds per pen. A mild challenge was introduced by oral gavage at day five to the challenged birds, using a six-fold concentration of coccidial vaccine. A high fibre basal diet formulated with rye and wheat middlings was used to further increase the challenge. Body weight and feed intake were measured and feed conversion ratio (FCR) was calculated during starter (1–12 d), grower (12–21 d) and overall 1–21 days. Intestinal morphology and immune response parameters were measured on day 12 and 21. Compared to the unchallenged groups, the coccidial challenge reduced (P < 0.05) body weight gain (BWG), increased FCR, reduced villus height and increased crypt depth. The challenged birds had increased pro-inflammatory cytokines (IL-6, IL-1β; P < 0.05) in the intestine as well as higher levels of acute phase proteins (APP, haemopexin and α−1-acid glycoprotein) in the plasma and circulating heterophils. XAP + DFM supplementation improved BWG, reduced FCR and increased energy efficiency compared to the non-supplemented groups. The combination of XAP and DFM reduced inflammatory responses such as APP compared to the challenged control group and maintained performance to a comparable level seen in the unchallenged control. The data indicate that XAP enzymes in combination with Bacillus-based DFM may reduce the damage and performance losses induced by coccidial challenge.