An 8-week feeding trial was conducted to evaluate the effect of replacing soybean meal (SBM) with cottonseed meal (CSM) on growth and health of grass carp. Four isonitrogenous diets containing 0, 16.64, 32.73 and 48.94% of CSM, respectively, as replacements of 0, 35, 68 and 100% of SBM were fed to fish (initial body weight 7.14 ± 0.75 g/fish) in triplicate aquaria twice daily. The results indicated that fish fed diet containing 16.64% CSM as a replacement of 35% of SBM was not affected in weight gain (WG), feed efficiency ratio (FER) and feed conversion ratio (FCR) (P>0.05), while fish fed diets containing higher level of dietary CSM (32.73 and 48.94%) significantly decreased WGand PER and significantly increased FCR (P<0.05). Fish fed diets containing 16.64% of CSM had significantly increased hematocrit (Ht) and hemoglobin (Hb) values compared with fish fed with other diets (P<0.05). The activity of catalase (CAT), glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD), gene expression levels of GSH-Px and CAT, and content of malondialdehyde (MDA) were significantly lower for fish fed diets containing 16.64% CSM compared with fish fed other diets (P<0.05). These results showed 16.64% CSM could be used to replace 35% SBM in the diets of juvenile grass carp and without health impact.