The emergence and spread of pathogens pose significant challenges to the sustainability and productivity of aquaculture globally. For the Chilean salmon farming industry, salmonid rickettsial septicemia (SRS), caused by the facultative intracellular bacterium Piscirickettsia salmonis, constitutes one of the main disease challenges. In this study, the efficacy of various oral doses of florfenicol (FFC) (5, 7.5, and 10 mg/kg BW/day) against SRS was assessed in Atlantic salmon, when treatment was initiated at an early stage of infection. Since salmonids infected with P. salmonis typically lose appetite as the disease progresses, and the therapeutic FFC dose is dependent on a normal specific feeding rate (SFR), the treatments were administered 5 days post-challenge (DPC5). On the day of challenge, experimental fish were intraperitoneally (IP) injected with 0.2 mL of P. salmonis genogroup LF-89 inoculum (9.07 × 10⁷ CFU mL⁻¹). Fish mortality, behavior, clinical signs of disease, feed intake and SFR were monitored throughout the study. Conclusions: An important finding in this study was that all tested antibiotic doses halted disease progression and prevented mortality in fish challenged with P. salmonis when administered DPC5. In the control group, mortality reached 32.2% with fish displaying clinical signs of SRS.