A 3 × 3 factorial study examined the performance, endogenous enzyme activities and apparent ileal digestibility of nutrients, including energy, protein, starch, dry matter, amino acids and minerals of birds fed diets containing graded levels of cottonseed meal (CSM) with or without microbial enzymes. Nine iso-caloric and iso-nitrogenous diets were formulated mainly from wheat/sorghum/soybean meal. Three levels of CSM none (0%), low (5%, 10%, and 15%) or high (6%, 12%, and 18%) in the starter, grower, and finisher diets, respectively, were included. The diets were supplemented with three levels of a composite xylanase and beta-glucanase product at 0, 100 or 150 mg/kg diet. Each of the nine dietary treatments was randomly assigned to 6 replicates, with 10 birds per replicate. Feed intake (FI) and weight gain (WG) were recorded on day 10, 24 and 35, and feed conversion ratio (FCR) was obtained from the data, while enzyme activities and nutrient digestibility were measured on samples collected on day 10 and 24, and day 24 only, respectively. Feed intake up to day 35 decreased (P < 0.05) significantly with increasing enzyme supplementation. On the CSM-containing diets, enzyme supplementation at 100 or 150 mg/kg improved WG up to day 24, with the heaviest birds (1514 g/b) observed in the low CSM with 100 mg/kg enzyme group. Enzyme supplementation improved (P < 0.01) FCR all through the growth phases and also improved (P < 0.05) ileal crude protein and starch digestibility. High levels of CSM decreased the digestibility of starch, but this was improved (P < 0.05) by enzyme supplementation, showing an interaction between CSM and microbial enzyme on starch digestibility. The digestibility of arginine, glutamic acid and threonine improved with increased CSM inclusion, and that of methionine improved with increased enzyme supplementation. There was an interaction effect (P < 0.01) between CSM and enzyme on magnesium digestibility. Cottonseed meal inclusion improved the digestibility of copper and potassium and reduced the digestibility of phosphorus, while that of calcium and manganese was increased (P < 0.01) with enzyme supplementation. At day 10, lipase activity was increased (P < 0.05) by higher CSM levels, while on day 24, general proteolytic activity was highest (P < 0.05) when 100 mg enzyme was supplemented in the diet. These results indicate that relatively high levels of CSM in diet have no negative effects on the growth and digestive physiology of broiler chickens when supplemented with xylanase and β–glucanase.