The present study was conducted to evaluate the effects of astaxanthin (AST) against lipopolysaccharide (LPS)‐induced lymphocyte viability, ultrastructural lesions, apoptosis, oxidative stress and inflammatory responses in Channa argus. Lymphocytes exposed to more than 10 μg/ml LPS alone for 24 hr showed significantly decreased cell viability, elevated nitric oxide (NO) and malondialdehyde (MDA), lactate dehydrogenase (LDH) contents, and increased nuclear factor κB p65 (NF‐κB p65), myeloid differential protein‐88 (MyD88), tumour necrosis factor‐α (TNF‐α), interleukin‐1β (IL‐1β), interleukin‐8 (IL‐8), caspase‐3, caspase‐8 and caspase‐9 gene expression. LPS at a concentration of 10 μg/ml could induce oxidative stress and inflammatory responses in lymphocytes. The activities of antioxidant enzymes (catalase (CAT), glutathione peroxidase (GPx), superoxide dismutase (SOD)) were significantly decreased after exposure to 10 μg/ml LPS. Besides, AST strikingly antagonized the LPS‐induced negative effects. AST significantly increased the expression of HSP70, HSP90, IκB‐α, and glucocorticoid receptor (GR) and decreased inflammatory responses. Further study showed that AST can activate GR signalling pathway and inhibit p65 phosphorylation. In addition, AST attenuated LPS‐induced apoptosis, mitochondrial swelling, degeneration and vacuolization. Collectively, these findings suggest that AST has protective roles in LPS‐induced cell damage via modulating GR activation in C. argus lymphocytes.