The current study was conducted to assess the ability of chitosan and nanoparticles of chitosan to alleviate the effect of heavy metals in Oreochromis niloticus. The experimental design was completely randomized with a 2 x 3 factorial design; two protein sources; fish and gluten meals, and three forms of chitosan (zero-chitosan, chitosan, and chitosan nanoparticles). A total number of 270 O. niloticus fingerlings were randomly distributed among 18 tanks (water capacity=55 liters). The overall duration of the experiment was 82 days. Results revealed that fish fed on a fish meal-based diet recorded the highest retained heavy metals followed by those fed gluten meals. Moreover, supplementation of diets with chitosan and chitosan nanoparticles lowered the concentration of the retained heavy metals in the fish's whole body, especially chitosan nanoparticles. Consequently, it is recommended to use CS and CSNP, especially chitosan nanoparticles as feed additives for fish cultured in agricultural and sewage wastewaters, loaded with high concentrations of heavy metals to ameliorate the fish quality.