This study investigated the interactive effects of ammonia nitrogen (AN) and nitrite stress on largemouth bass (Micropterus salmoides) in the context of Edwardsiella piscicida (E. piscicida) infection. The results indicated that a combined stress of 2 mg/L nitrite initially induced a short-term immune enhancement in the host. This enhancement was characterized by the activation of genes associated with antigen recognition (CD40, TLR-2, IgM, and IFN-γ), innate immunity (MsP-2 and HSP70), inflammatory factors (IL-8 and TNF-α), and autophagy (VAMP8 and STX17) in the gills, liver, and head kidney tissues. However, this immune response gradually weakened with prolonged exposure. Conversely, a high concentration of AN (24.0 mg/L) significantly suppressed the expression of most immune-related genes, leading to an imbalance in the regulation of autophagy and apoptosis, oxidative damage, and exacerbated histopathological changes, including hepatocyte necrosis, renal hemorrhage, and granuloma formation. Under high nitrite stress (20.0 mg/L), the modulation of immune genes exhibited tissue-specific differences, resulting in severe pathological damage such as lamellar fusion in gills, spleen necrosis, and liver vacuolization. Further enzymatic activity analysis revealed that fish under single E. piscicida infection enhanced their anti-infection and anti-oxidation capabilities by increasing MPO and SOD activities in various tissues, whereas the combined stress of high AN (24.0 mg/L) inhibited these activities. Under high nitrite stress, ACP and MPO activities in various tissues, as well as serum SOD activity, were significantly lower than those observed in the single infection group. The findings suggest that IFN-γ, MsP-2, and HSP70 play crucial roles in both anti-infection and stress responses.