The transcriptomic response of the sea louse Caligus rogercresseyi during the infestation on Atlantic salmon (Salmo salar) and coho salmon (Oncorhynchus kisutch) was evaluated using 27 genes related to immune response, antioxidant system and secretome. Results showed early responses of TLR/IMD signaling pathway in sea lice infesting Atlantic salmon. Overall, genes associated with oxidative stress responses were upregulated in both host species. This pattern suggests that reactive oxygen species emitted by the host as a response to the infestation, could modulate the sea louse antioxidant system. Secretome-related transcripts evidenced upregulation of trypsins and serpins, mainly associated to Atlantic salmon than coho salmon. Interestingly, cathepsins and trypsin2 were downregulated at 7 days post-infection (dpi) in coho salmon. The principal component analysis revealed an inverse time-dependent pattern based on the different responses of C. rogercresseyi infecting both salmon species. Here, Atlantic salmon strongly modulates the transcriptome responses at earlier infection stages; meanwhile coho salmon reveals a less marked modulation, increasing the transcription activity during the infection process. This study evidences transcriptome differences between two salmon host species and provides pivotal knowledge towards elaborating future control strategies.