Peracetic acid (PAA), a strong organic peroxide, is considered a relatively sustainable disinfectant in aquaculture because of its broad effectivity against many pathogens at low concentrations and because it degrades spontaneously to harmless residues. The impacts of PAA on fish health must be determined before its use as either a routine disinfectant or chemotherapeutant. Here we investigated the systemic and mucosal stress responses of Atlantic salmon (Salmo salar) to PAA. In experiment 1, salmon were exposed to different nominal concentrations (0, 0.6, and 2.4 ppm) of PAA for 5 min, followed by a re-exposure to the same concentrations for 30 min 2 weeks later. Sampling was performed before exposure to PAA and at 2 h, 48 h, and 2 w after exposures. In experiment 2, fish were subjected to crowding stress prior to PAA exposure at 4.8 ppm for 30 min. The fish were sampled before exposure and 1 h, 4 h, and 2 w after. The two trials were performed in a recirculation system. Both systemic (i.e., plasma cortisol, glucose, lactate, total antioxidant capacity) and mucosal (i.e., expression of antioxidant coding genes in the skin and gills) stress indicators were affected by the treatments at varying levels, and it was apparent that the fish were able to mount a robust response to the physiological demands of PAA exposure. The cortisol levels increased in the early hours after exposure and returned to basal level afterwards. Prior exposure history to PAA did not markedly affect the levels of plasma lactate and glucose when fish were re-exposed to PAA. Crowding stress before PAA treatment, however, did alter some of the stress indicators (i.e., lactate, glucose and expression of antioxidant genes in the gills), suggesting that stress history serves as both a confounding and compounding factor on how stress responses to PAA are mobilised. Nonetheless, the changes were not substantial. Gene expression profile analyses revealed that the antioxidant system was more responsive to PAA in the gills than in the skin. The increased antioxidant capacity in the plasma, particularly at 2.4 ppm and higher, indicates that antioxidants were produced to neutralise the internal redox imbalance resulting from PAA exposure. In conclusion, the results show that salmon were able to mount a robust adaptive response to different PAA doses and exposure times, and a combined exposure to stress and PAA. These results underscore the potential of PAA as a chemotherapeutant for salmon at PAA concentrations commonly applied to control parasitic infestations.