Brown trout (Salmo trutta fario) is a salmon subspecies that is a popular fish worldwide that is of great economic and food value. However, brown trout is not resistant to Aeromonas salmonicida, leading to substantial losses in the fishing industry due to the widespread presence of this bacterium in fresh and saltwater environments. This study elucidated how brown trout develop resistance to A. salmonicida and identify associated resistance genes. For this purpose, individuals with partial resistance to A. salmonicida were selected during the production process. The study compared cellular heterogeneity among three groups: the resistant, susceptible, and control groups. Head kidney tissues were extracted, and single-cell transcriptome sequencing was performed. The results revealed that the number of dendritic cells (DCs) and granulocytes was significantly lower in the susceptible group compared to the resistant and control groups after being exposed to A. salmonicida. Conversely, the susceptible group had a higher number of erythrocytes and macrophages than the resistant and control groups. In addition, the resistant group had a higher number of T cells than the susceptible and control groups. These differences can be attributed to the induced signal recognition of DCs and granulocytes, leading to pathogen recognition, phagocytosis, and subsequent death. Furthermore, the resistant group activated T cells through similar pathways, such as Fc γ R-mediated phagocytosis and Fc ε RI regulation. These findings provide a reference for further exploration of resistance genes in brown trout, thereby providing an enhanced understanding of the molecular mechanisms responsible for disease resistance in brown trout. Moreover, the results provide valuable genetic resources for breeding resistant brown trout varieties.