Abstract: The Gram-negative bacteria Edwardsiella piscicida and Flavobacterium columnare represent two major pathogens responsible for substantial losses in aquaculture. Outbreaks of these pathogens are often accompanied by marked fluctuations in dissolved oxygen (DO) levels. Therefore, we utilized Danio rerio and Pelteobagrus fulvidraco to investigate the effects of dissolved oxygen on host resistance against bacterial infections. In this study, based on the results of bacterial plate counts, the growth of the two pathogenic bacteria under aerobic conditions was better than that under low-oxygen conditions. The death of Danio rerio and Pelteobagrus fulvidraco infected by two pathogenic bacteria under normoxic and hypoxic conditions also indicated that hypoxia inhibited the resistance of the two fish species to E. piscicida and F. columnare, suggesting that low oxygen conditions may facilitate bacterial replication or colonization within host tissues. Further qRT-PCR experimental results indicated that hypoxia inhibited the production of tumor necrosis factor (TNF-α) and interleukins (IL-1β, IL-6) induced by E. piscicida (P<0.01) and F. columnare (P<0.05). In conclusion, these results demonstrate that hypoxia weakens the immune defense capacity of Danio rerio and Pelteobagrus fulvidraco against bacterial infections. 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.