Pseudomonas aeruginosa is an opportunistic pathogen that is correlated with persistent infections within wound environments. These infections are often recalcitrant to both antimicrobial treatments and host immune defenses. Development of novel therapies therefore is critical. Herein, we demonstrate the therapeutic potential of well characterized phages, PEV2 and φKMV, as promising strategies for controlling P. aeruginosa infections in a murine wound infection model. We also focus on the interactions between phages, bacteria, and immune system that currently are unclear but important for the understanding and development of phage-based therapies. Phage φKMV monotherapy improved P. aeruginosa-infection outcomes by decreasing bacterial burden within the wound bed 72 h post-infection by 4 logs and 3.4 logs for the PAO1 reference strain and a clinical wound isolate, respectively. Phage PEV2 reduced PAO1 infection by 2.9 logs but reduced the wound isolate burden by only 1 log. When phage-phage combination therapy was applied, the two phages seem to have interfered with each other as the bacterial burden of wound isolate was reduced by only 2 logs. Immunologically, untreated wound neutrophil numbers were found to be substantially elevated in both the blood and wounds of infected mice, while phage treatment lowered those levels. This suggests that phage-related decreases in bacterial burdens result in lower neutrophil recruitment. Improved healing and overall reduced levels of inflammatory markers were also observed with phage treatment in comparison to untreated wound infections. This was inferred from the correlation of treatment with eradication of bacteria and downregulation of the activity of cells engaged in proinflammatory processes. Histopathology analysis of the PAO1-infected wound tissue showed necrosis extending from remaining superficial dermis to the panniculus carnosus, while phage treatment presented reduced necrosis. We additionally investigated bacterial resistance to phages as they evolved during treatments. Different types of bacterial mutants arose due to changes in transcription regulation, type II secretion, and DNA gyrase function as well as flagellar and LPS biosynthesis, among others. Currently we are studying metabolomic changes within the blood and wound bed during infections and treatments. This proof-of-concept pre-clinical study will provide a platform for translation to human studies targeting P. aeruginosa and other problematic multidrug-resistant wound pathogens as well as provide a unique perspective on microbial dynamics and metabolic response to infection and phage therapy. Keywords: phage therapy, Pseudomonas, wound model