The goal of the current study is to evaluate the potential of marine phages for therapy of motile Aeromonas septicemia caused by Aeromonas hydrophila in Nile tilapia (Oreochromis niloticus). To achieve this goal, four different Aeromonas phages namely AP1, AP2, AP3 and AP4 were isolated from seawater samples and tested for their potentiality as antibacterial agents against culture community in aquaculture water using RAPD-PCR. Results showed significant variation in their antibacterial effect. Characterization of the isolated phages based on restriction digestion using  EcoRI, Bam HI, HindIII and Eco RV restriction enzymes and RAPD-PCR proved that the phages were not identical. Plackett Burman experimental design was applied for optimization of culture conditions to improve the antibacterial activity of the most promising AP2 phage against A. hydrophila. Results achieved 94% elimination of A. hydrophila comparing to phage infectivity under basal conditions. Invivo efficiency of AP2 against A. hydrophila invading the aquaria of Nile tilapia was investigated. Elimination of A. hydrophila in the rearing water was detected after 24h. Moreover, morphological and histological examination of the tested liver and gills tissues of Nile tilapia proved the promising effect of AP2 for therapy of motile Aeromonas Septicemia induces by A. hydrophila.