Edwardsiella piscicida is a Gram negative, invasive and intracellular pathogen lead to develop hemorrhagic septicemia in wide varieties of freshwater fish species worldwide. Previously, two novel E. piscicida mutant strains namely ΔphoP and ΔphoQ were constructed and the data were published. In the present study, the resistance of in-frame deleted mutant strains ΔphoP/Q were investigated for their immunogenicity at the levels of blood and serum killing activities in comparison with E. piscicida wild-type (WT) pathogenic strain C07-087. Moreover, tissue persistence and expression profile of some immune relevant genes were monitored in head kidneys, spleens and livers of the intra-peritoneal immunized channel catfish fingerlings model. Results revealed that ΔphoP and ΔphoQ showed a significant decreased resistance against host killing activities compared to E. piscicida WT strain. At all tested levels, the tissue persistence showed that the mutants held the capability to attack and spread in the immunized channel catfish investigated tissues. Meanwhile, live bacteria could be noticed in livers, spleens and anterior kidneys up to 7 days after immunization. Furthermore, significant up-regulation levels of IL-1β, INFγ, CD4-1, MHC class I and MHC class II were detected in anterior kidneys and spleens of WT, ΔphoP and ΔphoQ vaccinated fish compared to non-immunized control group at 14 and 21 days post immunization. In conclusion, our findings proved that ΔphoP and ΔphoQ mutant strains have the aptitude to motivate both innate and adaptive immune responses and also they have the prospective requirements as successful live vaccine candidates.