This study was designed to investigate the effect of Neem seed oil on the oxidative stress in gills and erythrocytes (EC), after 1, 2 and 3 weeks (W) and to evaluate the antioxidant effect of lupine seed supplementation (LS) in the Nile tilapia   Oreochromis niloticus. Two doses of Neem oil; 1/20 LC50:56 (NO1) and 1/10 LC50:112 PPM (NO2) and three periods of one, two and three weeks were used. Oxidative stress parameter, total peroxide (TP) and antioxidant enzyme activities, catalase (CAT) and superoxide dismutase (SOD) as well as glycemia were measured. NO2 markedly decreased CAT and SOD activities in gills at most periods (52 - 99% and 16 – 52 %, respectively) and in EC (22 - 62 and 48 – 63 %, respectively) in most periods, but NO1 had less effect. In turn, both doses significantly enhanced TP levels in gills and EC. Moreover, hyperglycemia was detected three weeks after control (NO) exposure. LS significantly curtailed or abolished the adverse effect of NO exposure on oxidative and antioxidant parameters in gills and EC. This may be attributed to the hypoglycemic effect of LS as well as its antioxidant efficiency. In conclusion, NO exerts oxidative damage in the fish and LS has an antioxidant potency.