Pseudomonas spp. causes significant losses in aquaculture, consecutive use of antibiotics, and reveals bacterial resistance; therefore, therapeutic bacteriophages, commonly called phages, are a promising potential alternative to antibiotics in the management of bacterial infections of a wide range of organisms, including cultured fish. The novelty of current work is represented in examining the lytic activity of four phages and their combination compared to the antibiotic streptomycin on Pseudomonas aeruginosa-infected Nile tilapia (Oreochromis niloticus) while measuring the hematological and blood biochemical parameters as a response for phage therapy. This study evaluated the in vitro killing curve for each phage using a growth curve that measured the OD600 after a single phage suspension was combined with the host P. aeruginosa, considered the best multiplicity of infection (MOI) for each phage. A144 healthy fish were acclimatized in the laboratory and divided into six groups: control, P. aeruginosa-infected fish, streptomycin, phage Ps1, Ps2, both (Ps1 and Ps2), were added to the T3, T4, T5, and T6 groups, respectively. Our findings demonstrated that P. aeruginosa infection caused surface body hemorrhages, tail and fin rot, irritated skin, superficial ulcers, and 100% mortality through 14 days. P. aeruginosa caused a reduction in hemoglobin (Hb), red blood cells (RBCs), platelet number (PLt), and platelet crit (PCT) count, protein, albumin, and A/G ratio; however, an increase in hematocrit (Hct), red cell distribution width (RDW), PDW, MPV compared to other groups after three days of infection and the effects increased after 12 days post-infection. The fish vaccinated with P1 (T4) and P1+P2 (T6) showed enhanced levels of Hb, RBCs, PLt, PCt, protein, albumin and decreased levels of RDW, PDW, MPV, and liver and kidney enzymes with enhanced contents more than streptomycin and closer to the control group. The biochemical markers recorded significant changes indicating liver and kidney impairments due to the infection with P. aeruginosa. It can be concluded that P1 and P1+P2 combinations could be used as therapy in Pseudomonas-infected fish to enhance their blood parameters and performance.