Three 2à 2 factorial experiments (EXP) were conducted to investigate the underlying mechanism of corn quality and a supplemented cocktail enzyme of amylase, protease, and xylanase on broiler performance from 0 to 49 days of age. In each of the first two EXP, the four diets used consisted of (1) diet AR-/BR-; reduced dietary energy by increasing corn A matrix metabolizable energy (ME) 138 kcal/kg in EXP 1 or 125 kcal/kg ME with corn B in EXP 2; (2) diet AR+/BR+; AR-/BR- plus Avizyme 1502® (AZ); (3) diet AN-/BN-; normal energy diet; (4) diet AN+/BN+; AN-/BN- plus AZ. In EXP 3, four dietary treatments came from EXP 1 and 2 consisted of: AN-, AN+, BN-, and BN+. For each EXP, 1,440 male Ross 708 chicks were randomly assigned to one of the four dietary treatments (trts) with 9 replicates (reps)/trt and 40 chicks/ rep on day (d) 0. Body weight gain (BWG) and feed intake (FI) were determined on feed change days (d 14, 28, and 37) and on d 7 and 49. On d 28, subsets of birds were transferred to Petersime batteries to evaluate feed passage rate and nutrient retention. Digesta samples from gizzard, jejunum, and ileum as well as pancreatic tissue samples were collected for analyses of amylase, protease, and xylanase activities. Intestinal tissue samples were collected for determination of maltase, sucrase, and aminopeptidase N activities. Jejunal tissue on d 28 was also collected for total RNA isolation and a subsequent genome-wide microarray assay. On d 50, 54 birds per trt were processed to evaluate carcass yield. Interactions of ME and AZ were observed in both EXP 1 and 2. In EXP 1, interactions of ME and AZ on BWG were observed with higher values in birds fed AN- while lower in birds fed AN+, while opposite observations in EXP 2 with corn B diets. In both EXP 1 and 2, feed conversion ratio (FCR) in birds fed normal energy diets was better (P <0.05) as compared to birds fed reduced energy diets after d 28. Percent fatpad was increased (P <0.05) with dietary energy levels in EXP 1. Percent pectoral minor was increased (P <0.05) in birds fed AZ diets (4.80 vs. 4.62%). In EXP 3, interaction of dietary corn and AZ (P < 0.05) on BWG was noted during d 14 and 37. Birds fed corn B diets had better (P < 0.05) BWG and feed efficiency as compared to birds fed corn A diets until d 14. Nitrogen retention on d 30 was greater (P < 0.05) in birds fed AN- and BN+ as compared to birds fed AN+ and BN-. A 2.8% more apparent metabolizable energy with nitrogen correction (AMEn) in corn A diets was observed as compared to corn B diets. Corn A had higher amylase and xylanase activities as compared to corn B. Xylanase activity in jejunal and ileal digesta of birds fed corn A diets were higher (P < 0.05) as compared to that of corn B birds on d 7 and 49. Sucrase-isomaltase contributed 63, 80, and 74 % of the total maltase activity in duodenum, jejunum, and ileum. Sucrase activities in duodenum and jejunum were correlated (P < 0.05) with performance, whereas duodenal aminopeptidase N was negatively correlated (P < 0.05) with performance except period BWG. Pancreatic amylase and protease as well as gizzard protease and xylanase activities were correlated (P < 0.05) with performance. Number of jejunal genes regulated (P < 0.05) by corn variety was 77 as compared to those by enzyme supplementation in corn A diets (30 genes) and corn B diets (23 genes). Immune response and metabolism related genes were the most regulated genes in birds fed different corn diets without enzyme addition. In conclusion, enzyme supplementation improved broiler performance. Dietary formulation strategy using either reduced energy or normal energy in associated with enzyme supplementation should base on the feed ingredient quality. Corn quality may come from active components such as protease inhibitor and xylanase, and improved performance in birds fed high quality corn diets might also relate with minimal immune response and metabolic demand.