Abstract: This study aims to utilize Danio rerio and Pelteobagrus fulvidraco models, to explore the influence of changes in dissolved oxygen concentration in water bodies on the ability of fish to resist Edwardsiella piscicida and Flavobacterium columnare infections. The plate count method revealed that the in vitro growth of the two pathogenic bacteria was better under normal oxygen conditions than under hypoxic conditions. In vivo infection experiments have shown that compared with the normoxic group, hypoxic treatment significantly weakened the resistance of Danio rerio and pelteobagrus fulvidraco to two pathogenic bacteria, leading to an increase in mortality. qRT-PCR analysis revealed that hypoxia inhibited the gene expression of key inflammatory factors (TNF-α, IL-1β, IL-6) induced by Edwardsiella piscicida (P<0.01) and Flavobacterium columnare (P<0.05). In conclusion, although hypoxia inhibits the in vitro growth of pathogenic bacteria to a certain extent, in the host body, hypoxia significantly weakens the fish's immune defense ability by suppressing the key inflammatory immune response, ultimately leading to a higher infection mortality rate. This research helps to prevent the occurrence of pathogenic bacteria in aquaculture by regulating the dissolved oxygen concentration in water bodies, thereby providing a new perspective for aquatic health management.