The alarming rise of multi-drug resistant microorganisms has increased the need for new approaches through the development of innovative agents that are capable of attaching to the outer layers of bacteria and causing permanent damage by penetrating the bacterial outer membrane. The permeability (disruption) of the outer membrane of Gram-negative bacteria is now considered to be one of the main ways to overcome multidrug resistance in bacteria. Natural and synthetic permeabilizers such as AMPs and dendritic systems seem promising. However, due to their advantages in terms of biocompatibility, antimicrobial capacity, and wide possibilities for modification and synthesis, highly branched polymers and dendritic systems have gained much more interest in recent years. Various forms of arrangement, and structure of the skeleton, give dendritic systems versatile applications, especially the possibility of attaching other ligands to their surface. This review will focus on the mechanisms used by different types of dendritic polymers, and their complexes with macromolecules to enhance their antimicrobial effect, and to permeabilize the bacterial outer membrane. In addition, future challenges and potential prospects are illustrated in the hope of accelerating the advancement of nanomedicine in the fight against resistant pathogens.