A. salmonicida is one of the oldest known marine pathogens with an increasing host-range from freshwater to marine fish species, mainly affecting salmonids, and currently emergent cultured fish species such as lumpfish, Atlantic cod, sablefish. A. salmonicida infection causes furunculosis, resulting in a systemic shock, organ failure and ultimately death. Understanding A. salmonicida infection development at early stages is critical for the disease output, including intracellular infection, immune response elusion, and propagation to lymphoid organs. Here, we performed a semi-dual RNA-seq based technology to identify relevant genes for A. salmonicida early infection in real-time in Atlantic salmon primary macrophages. RNA samples were taken after 1 h post-infection and 2 h post-infection, mimicking cellular attachment and intracellular infection. We identified a total of 871 differential expressed genes (DEGs) at 1 hpi and a total of 1,683 DEGs were identified at 2 hpi. Gene ontology (GO) of these DEGs during the attachment of A. salmonicida to the host cell showed a negative impact on the expression of genes related to cellular stimulus and biological processes, ion binding and integral components of the membrane. In contrast, during an early infection process, expression of genes associated with cytoskeleton organization and actin polymerization, phospholipid binding, plasma membrane organization, cytokine activity, inflammatory response, wound healing, calcium transport and RNA polymerase II transcription factor activity are modulated. The enrichment of KEGG pathways showed that A. salmonicida hijacks pathways related to innate immune response, lipids synthesis, gene transcription, cellular arrest, and apoptosis, mainly affecting cytokine-cytokine receptor interaction and protein processing endoplasmic reticulum, toll-like receptor signaling, RIG-1-like signaling, p53, and necroptosis pathways. These indicate that A. salmonicida induces and modulates phagocytosis and apoptosis to survive in an intracellular environment during the early stages of furunculosis.