A. salmonicida subsp. salmonicida is one of the oldest-known marine pathogens causing furunculosis in freshwater to marine fish species. A. salmonicida causes septicemia and fish death due to a systemic shock. Early stages of A. salmonicida infection, including intracellular macrophage infection, are not fully comprehended. Here, we conducted a dual RNA-seq study and functional analyses in Atlantic salmon primary macrophages infected with A. salmonicida to identify relevant genes for fish cellular immunity and A. salmonicida pathogenesis. At 1-h post-infection (hpi), A. salmonicida modulated the expression of genes associated with inflammation, fatty acids synthesis, and apoptosis. While at 2 hpi A. salmonicida hijacked pathways related to myeloid cell differentiation, cytoskeleton and actin filament organization, lysosome maturation, and apoptosis. In contrast, A. salmonicida upregulated genes encoding for hemolysin, aerolysin, type IVa pili, and T3SS effectors. In conclusion, these results suggest that A. salmonicida induces endocytosis, impairs lysosome maturation, and reduces apoptosis.