Abstract This study aimed to evaluate the growth performance and animal health in juveniles of Nile tilapia (Oreochromis niloticus) fed a practical diet with total replacement of fishmeal (FM) by soybean meal, as well the effect on survival, following pathogenic challenge with Aeromonas hydrophila. Two hundred juveniles of Nile tilapia were stored in 8 tanks (800 L). The experiment consisted of two treatments: a commercial diet formulated with FM (control) and a practical diet with total replacement of FM by soybean meal (SM). The variables of water quality, zootechnical and hematological parameters were measured. In addition, at the end of the experiment, the fish were submitted to a challenge with A. hydrophila. Higher cost per kg of fish was obtained in the control treatment (with FM). N retention was higher in fish fed a diet without FM, while hematological, immunological parameters and survival after the experimental challenge did not differ between treatments. It is possible to reduce dietary costs by replacing FM with SM without affecting growth performance or animal health, in addition to benefiting the environment by reducing the excretion of N in water.