Multi-drug resistant (MDR) enteric bacteria are of increasing global concern. A clonal group, Escherichia coli sequence type (ST) 131, harbors both MDR and a deadly complement of virulence factors. Patients with an immunocompromised system are at high risk of infections with these E. coli and there is strong epidemiologic evidence that the human intestinal tract, as well as household pets, may be a reservoir. Here, we examine if phages are an effective treatment strategy against this clonal group in murine models of bacteremia that recapitulate clinical infections. Bacteriophages isolated from known E. coli reservoirs lyse a diverse array of MDR ST131 clinical isolates. Phage HP3 reduced E. coli levels and improved health scores for mice infected with two distinct ST131 strains. Efficacy was correlated to in vitro lysis ability by the infecting phage and the level of virulence of the E. coli strain. Importantly, it is also demonstrated that E. coli bacteremia initiated from translocation across the intestinal tract in an immunocompromised host is substantially reduced after phage treatment. This study demonstrates that phage, isolated from the environment and with little experimental manipulation, can be effective in combating even the most serious of infections by E. coli "superbugs".