The effects of a dietary protease‐complex on growth performance, body composition, digestive and immune enzyme activity of Litopenaeus vannamei and its resistance to a pathogenic Vibrio parahaemolyticus were assessed in a 9‐week trial. A high fish meal diet (HF) containing 200 g kg−1 fish meal and a low fish meal diet (LF) containing 100 g kg−1 fish meal were designed as a positive and negative control respectively. Three other diets (LF+125P, LF+150P, and LF+175P) were manufactured by supplementing graded level of a protease‐complex (125, 150 and 175 mg kg−1, respectively) to the LF diet. All diets were formulated to be iso‐proteic and iso‐energetic. Most performance indices of shrimp fed the LF+175P diets were similar to the HF diet. Among the digestive enzymes, trypsin, lipase and amylase activity in hepatopancreas of shrimp fed LF+175P diets (4576 U mg−1 protein and 16, 32 U g−1 protein, respectively) were higher than those fed the LF diets but lower than the HF diets (P < 0.05). Total superoxide dismutase and polyphenol oxidase contents in both serum and hepatopancreas were higher and serum malondialdehyde content and the cumulative mortality during disease challenge tests were lower for the diets containing the protease‐complex than those fed the LF diets (P < 0.05) with no difference with those fed the HF diets.