Piscirickettsiosis is the main bacterial disease affecting the Chilean salmon farming industry and is responsible for high economic losses. The development of effective strategies to control piscirickettsiosis has been limited in part by insufficient knowledge of the host response. The aim of this study was to use RNA sequencing to describe the transcriptional profiles of the responses of post-smolt Atlantic salmon infected with LF-89-like or EM-90-like Piscirickettsia salmonis. Enrichment and pathway analyses of the differentially expressed genes revealed several central signatures following infection, including positive regulation of DC-SIGN and TLR5 signalling, which converged at the NF-κB level to modulate the pro-inflammatory cytokine response, particularly in the PS-EM-90-infected fish. P. salmonis induced an IFN-inducible response (e.g., IRF-1 and GBP-1) but inhibited the humoral and cell-mediated immune responses. P. salmonis induced significant cytoskeletal reorganization but decreased lysosomal protease activity and caused the degradation of proteins associated with cellular stress. Infection with these isolates also delayed protein transport, antigen processing, vesicle trafficking and autophagy. Both P. salmonis isolates promoted cell survival and proliferation and inhibited apoptosis. Both groups of Trojan fish used similar pathways to modulate the immune response at 5 dpi, but the transcriptomic profiles in the head kidneys of the cohabitant fish infected with PS-LF-89 and PS-MS-90 were relatively different at day 35 post-infection of the Trojan fish, probably due to the different degree of pathogenicity of each isolate. Our study showed the most important biological mechanisms used by P. salmonis, regardless of the isolate, to evade the immune response, maintain the viability of host cells and increase intracellular replication and persistence at the infection site. These results improve the understanding of the mechanisms by which P. salmonis interacts with its host and may serve as a basis for the development of effective strategies for the control of piscirickettsiosis.