The One Health approach emphasizes the importance of antimicrobial resistance (AMR) as a major concern both in public health and in food animal production systems. As a general classification, E. coli can be distinguished based on the ability to cause infection of the gastrointestinal system (IPEC) or outside of it (ExPEC). Among the different pathogens, E. coli are becoming of great importance, and it has been suggested that ExPEC may harbor resistance genes that may be transferred to pathogenic or opportunistic bacteria. ExPEC strains are versatile bacteria that can cause urinary tract, bloodstream, prostate, and other infections at non-intestinal sites. In this context of rapidly increasing multidrug-resistance worldwide and a diminishingly effective antimicrobial arsenal to tackle resistant strains. ExPEC infections are now a serious public health threat worldwide. However, the clinical and economic impact of these infections and their optimal management are challenging, and consequently, there is an increasing awareness of the importance of ExPECs amongst healthcare professionals and the general public alike. This review aims to describe pathotype characteristics of ExPEC to increase our knowledge of these bacteria and, consequently, to increase our chances to control them and reduce the risk for AMR, following a One Health approach.