Multidrug resistance in Gram-negative bacteria has become a significant global public health challenge, threatening human health and clinical treatment outcomes. The unique outer membrane structure of these pathogens greatly limits antibiotic penetration, serving as the core mechanism of resistance. This paper systematically analyses antimicrobial strategies targeting the outer membrane of Gram-negative bacteria, mainly including: (1) directly disrupting the outer membrane structure and enhancing drug permeability; (2) inhibiting the biosynthesis or transport pathways of key outer membrane components; (3) using natural pathways to facilitate drug entry into the cell; (4) inhibiting efflux pumps to block efflux functions; (5) optimizing the physicochemical properties of drugs to enhance outer membrane permeability and using nanotechnology to develop new drug delivery systems. In recent years, BAM complex inhibitors like darobactin and xenorceptides have efficiently blocked the assembly of outer membrane proteins through a novel mechanism and exhibited excellent broad-spectrum antibacterial activity. Iron carrier-conjugated drugs like cefiderocol have also successfully transitioned to clinical use, showing significant efficacy in treating infections caused by various multidrug-resistant bacteria. Despite promising strategies targeting the outer membrane, drug development faces challenges, such as poor selectivity, potential toxicity, and evolving resistance mechanisms. Future research must delve deeper into the biosynthesis and regulatory mechanisms of the outer membrane, aiming to develop more selective and safer innovative antimicrobial drugs and delivery systems to effectively combat the growing threat of multidrug-resistant Gram-negative bacterial infections.