Abstract: Enterohemorrhagic Escherichia coli (EHEC) is an important foodborne human pathogen that causes various severe intestinal diseases. Antibiotics are mainly used to control pathogenic bacteria. However, the extensive use of antibiotics increases antibiotics resistance and disrupts human flora, posing threats to public health security. Thus, it is necessary to develop alternative therapies to antibiotics. Phages are potential antibiotic alternatives with high host specificity, killing host bacteria without damaging other bacteria. However, the rapid emergence of phage-resistant bacteria remains a major challenge for phage therapy. Phage cocktails containing diverse phage strains have been identified as an effective strategy, although substantial isolation efforts are required which can be disadvantageous for treatments. In the ecosystem, phages adaptively evolve with bacteria. This process has been repeated in laboratory and diverse phage strains can be obtained. In this study, an Escherichia coli phage vB_EcoM_CRP22 (CRP22) is isolated but demonstrates poorly antimicrobial against EHEC. An iterative adaptive evolution strategy is designed to obtain different phage strains targeting phage-resistant EHEC. Multiple evolved phages complement its host spectrum, leading to the enhanced antimicrobial efficiency of phage cocktails against EHEC. The phage cocktail consisting of 6 phage strains effectively control the OD₆₀₀ value below 0.4 within 36 h post-infection. This work contributes to promoting the alternative of antibiotic therapies and provides a new insight into the development of phage therapy.