Abstract: China is the leading producer of tilapia in the world, with a production volume of 1.65 million tons in 2020. However, the tilapia industry in China is facing limitations due to streptococcosis caused by Streptococcus agalactiae, which has become one of the major factors with the increased culture density and the deterioration of culture environment. Breeding new varieties of tilapia resistant to streptococcosis is an important way to mitigate the disease. Different tilapia strains exhibit varying levels of disease resistance. Therefore, this study aimed to explore the tolerance of two blue tilapia species to S. agalactiae, Oreochromis aureus “Xia’ao No. 1” (AX strain) and Egypt strain (AE strain). The survival rate was recorded at different time points. Blood and spleen samples were collected at 0, 7h, 24h, 48h, 72h, 120h and 168h after infection, respectively. The serum biochemical indexes and expression of pro-inflammatory cytokines in spleen of two blue tilapia species were measured. The survival rate of AE strain (30%) was significantly higher than that of the AX strain (10%) at 7d post infection. The alanine aminotransferase (ALT), aspartate aminotransferase (AST), globulin (GLO), alkaline phosphatase (AKP), superoxide dismutase (SOD), lactate dehydrogenase (LDH) and lysozyme (LZM) in the serum of two blue tilapia species increased significantly after infection, whereas triglyceride (TG), albumin/globulin (A/G) decreased significantly. The infection resulted in a strong inhibition of the respiratory burst. The AE strain demonstrated significantly higher serum globulin and SOD levels compared to the AX strain at later stages of infection. The mRNA levels of pro-inflammatory cytokines in the spleen of two blue tilapia species were significantly up-regulated at 7h post infection. Moreover, the gene expression of TNF-α, IL-1β and IL-6 in spleen of AE strain was significantly lower than that observed in AX strain during the later stage of observed period. The study shows that the AE strain exhibits stronger resistance to S. agalactiae compared to the AX strain. The higher antioxidant capacity and less severe inflammation observed at later stages of infection contribute to the increased tolerance of AE strain to S. agalactiae. The results provide valuable parental resistance germplasm resources for breeding streptococcosis resistant hybrid tilapia.