Streptococcosis, a bacterial disease for multiple fish species, especially tilapia, caused more disruption to the fish culture industry. However, the underlying mechanisms for the occurrence of streptococcosis remain unclear. The aim of this study was to study the effects of streptococcus on the liver of tilapia. In this study, tilapia were injected streptococcal solution (0.05 ml/10 g body weight) and collected blood and liver at 4, 8, 24, 48, 72, 96, 120 and 144 hr after injection. The results showed that the activities of glutamate oxalate transaminase (GOT), glutamate pyruvate transaminase (GPT), alkaline phosphatase (AKP) and superoxide dismutase (SOD) in the serum of tilapia exhibited irregular changes: increase at first, then decrease and increase again. The levels of total antioxidant capacity (T‐AOC), glutathione (GSH) and malondialdehyde (MDA) showed a decreasing tendency in serum after injection, except GSH at 4 hr. The activity of catalase (CAT) decreased in serum at 4, 24, 120 and 144 hr after injection of streptococcal solution, while the content TP enhanced in serum at 48, 72 and 120 hr after injection. Observations of pathological sections showed obvious damage to the liver tissue structure in response to streptococcal infection. Western blotting revealed an increase in ikkbeta (Ikkβ) protein with prolonged infection time and a decrease in NF‐kappa‐B inhibitor alpha (IkB‐α) and ikappab kinase alpha (Ikkα) proteins. The gene expression of cytochrome P4501A (CYP1A) was downregulated in liver at 24 and 48 after injection, while the mRNA levels of heat stress protein 70 (HSP70) and tumour necrosis factor alpha (TNF‐α) increased at 48 and/or 72 hr. Taken together, our findings confirmed that streptococcus can cause serious damage to the liver of tilapia.