Abstract: To investigate the effects of dietary energy density (DED) and dietary feed ration (DFR) on fish growth and health, a 2×2 factorial experiment was designed, including 2 DED (control diet and high carbohydrate and fat diet) and 2 DFR (1 and 1.2 times energy level of fish fed to control diet apparent satiation). To evaluate the effects of DED and DFR on growth performance, feed utilization, body composition, hematological indices and resistant to Streptococcus agalactiae infection of genetically improved farmed tilapia, Oreochromis niloticus (14.59±0.06) g, the study set 40d as a cycle for 2 cycles (period Ⅰ and Ⅱ). The results showed that DED and DFR did not affect the feed efficiency (P>0.05), and DED did not affect the fish growth performance (P>0.05). High DFR improved the final mean weight (P<0.05), but reduced protein retention during period Ⅱ (P<0.05). DED and DFR had no impact on the conditional factor (P>0.05); in period Ⅰ, high DED only induced the viscerasomatic index (P<0.05), but in period Ⅱ, DED and DFR had significant effects on intestinal-somatic index and viscerasomatic index (P<0.05). High DED increased crude lipid content in the eviscerated whole fish and visceral mass (P<0.05); in period Ⅰ, high DFR enhanced crude lipid content in the liver (P<0.05), and in period Ⅱ, high DED and DFR induced crude lipid content in the eviscerated whole fish, liver, and muscle (P<0.05). High DED and DFR increased in the serum triglycerides and malondialdehyde content (P<0.05), and hematocrit in period Ⅰ(P<0.05), but it decreased the white cell count in period Ⅱ (P<0.05); high DED increased the serum alkaline phosphatase activity, and serum cholesterol (period Ⅱ) (P<0.05), but decreased the catalase and glutathione peroxidase activity (period Ⅰ) (P<0.05); high DFR increased the serum glucose levels (P<0.05). After infection with S. Agalactiae, DED and DFR did not affect the survival rate in period Ⅰ (P>0.05); however, high DFR decreased the survival rate in period Ⅱ (P<0.05). In conclusion, these results suggested that high DFR could improve the growth rate of tilapia, increase the fat deposition and reduce the health level of fish, and DED is more prone to fat deposition to impact fish health.