Zebrafish were used as a model to deeply analyze the immunological regulatory mechanism of fish resistance to Aeromonas hydrophila infection. CRISPR/Cas9 technology was used to construct a nr4a1 knockout. The histopathological analysis， qPCR， and transcriptome sequencing were combined to systematically study the role of nr4a1 in zebrafish resistance to A. hydrophila infection. The results showed that nr4a1^-/- zebrafish exhibited more severe histopathological damage to liver tissue and oxidative stress response after A. hydrophila infection compared to wild-type fish. The expression of pro-apoptotic genes including p53， bax， and caspase-9 was significantly upregulated in the livers of nr4a1^-/- zebrafish after infection， while the anti-apoptotic gene bcl-2 showed abnormal upregulation as well. The overexpression of nr4a1 gene in zebrafish ZF4 cells significantly inhibited the expression of the aforementioned apoptosis-related genes under infection conditions， indicating that Nr4a1 plays a role in inhibiting cell apoptosis during infection. It is indicated that Nr4a1 exerts immune protection by regulating cell apoptosis in zebrafish resistance to A. hydrophila infection.