Abstract: 【Objective】 This study compared the metabolic differences and key metabolic pathways between Zhuang-luo No. 1 tilapia and GIFT tilapia after the infection with Streptococcus agalactiae， aiming to provide reference for the molecular mechanism research on resistance of tilapia against Streptococcus agalactiae and disease resistant breeding in tilapia. 【Method】 When mortality rates of Zhuangluo No. 1 tilapia and GIFT tilapia after the infection with Streptococcus agalactiae were statistically analyzed， a liquid chromatography-mass spectrometry technology was applied to determine metabolites in head kidney， spleen， and liver during the infection with Streptococcus agalactiae at 0， 12， 24， and 48 h， through which the significantly differential metabolites （SDMs） in Zhuangluo No. 1 tilapia and their involved metabolic pathways were identified. 【Result】 Until the end of observation period （7 d），the mortality rate of Zhuangluo No. 1 tilapia （31.1%） was lower than GIFT tilapia （55.6%） after the infection with Streptococcus agalactiae. The PCA results indicated that the inter-sample difference among Zhuangluo No. 1 individuals was smaller than the GIFT ones at 12 h post the infection， since different metabolic profiles were observed between them before the infection. Quantity of the SDMs in both Zhuangluo No. 1 tilapia and GIFT tilapia peaked in head kidney at 12 h post the infection with Streptococcus agalactiae， while that peaked in spleen at 24 h post the infection. The up-regulated SDMs detected in head kidney of Zhuangluo No. 1 tilapia were significantly enriched in metabolic pathways of steroid biosynthesis， citrate cycle， and pyruvate metabolism， while the down-regulated SDMs were significantly enriched in metabolic pathways of steroid hormone biosynthesis， retinol metabolism， tryptophan metabolism. It was observed that the lysine degradation was activated in the head kidney of Zhuangluo No. 1 tilapia at 12 h post the infection when the content of key intermediate metabolite， N6-acetyl-L-lysine， was significantly increased （P<0.05）. 【Conclusion】 The disease resistance of Zhuangluo No. 1 tilapia was probably owing to its unique metabolic reprogramming by suppressing acute stress responses at the early stage of Streptococcus agalactiae infection. Insteadly， a sustained energy metabolism and membrane homeostasis regulatory networks are activated in head kidney. The L-serine antioxidant system and hexadecanal-mediated membrane protection mechanism work synergistically to achieve an efficient balance between immune defense and tissue protection， which provides a new metabolic target for disease-resistant breeding in fish.