To assess the impact of Chlorella vulgaris on the performance of the Nile tilapia, fish specimens with body weight 53.26 g ± 0.64 were fed on diets supplemented with 0, 5, 10, 15 and 20g of C. vulgaris for 60 days at a daily rate of 3% of body weight. The growth performance, feed conversion ratio, final weight, weight gain and daily weight gain were enhanced with supplemented levels up to 15g of C. vulgaris; while higher addition insignificantly differed with the other groups. Supplemented fish were well-nourished, and their health status was improved. Blood parameters {RBCs, WBCs, hemoglobin (Hg) and hematocrit (PCV)} were significantly higher than the control. Serum total protein and liver enzymes were significantly increased in supplemented fish; however, the levels of the liver enzymes revealed no adverse impact on liver health. C. vulgaris could stimulate the activities of antioxidants (catalase and total antioxidant capacity) and pro-inflammatory cytokines (interleukin-1β and tumor necrosis factor-α), improving the immune status. Fish that received C. vulgaris- supplemented diets had a higher survival rate against Aeromonas hydrophila infection, while the relative protection level (RPL) of florfenicol treatment was significantly improved compared to the control group.  It was obvious from the obtained results that the Nile tilapia could be fed up to 15g of C. vulgaris /kg fish feed without compromising the health status; it also enhanced the response of fish to florfenicol treatment raising the relative protection level to 42.86%.