Multidrug resistance (MDR) is a significant global challenge requiring strategic solutions to address bacterial infections. Recent advancements in nanotechnology, particularly in the synthesis of zinc oxide nanoparticles (ZnO NPs) using natural agents as stabilizers and reducing agents, have shown promising results in combating MDR. These nanoparticles possess strong antimicrobial properties against different strains of Gram-positive and Gram-negative, making them suitable for various industries, including food, pharmaceuticals, coatings, and medical devices. ZnO-NPs work by generating reactive oxygen species, releasing zinc ions (Zn2+), disrupting the bacterial cell membrane, interfering with metabolic processes and genetic material, and inducing oxidative stress and apoptosis. However, more research is needed to refine synthesis techniques, control size and morphology, and increase antibacterial efficacy. To fully understand their potential, interactions with proteins, DNA, and bacterial cell walls must also be examined. Investigating the synergistic potential of biogenic ZnO NPs with conventional antibacterial treatments could enhance therapeutic effectiveness while minimizing the risk of resistance emergence. Here we provide insight into the advancements in biogenic synthesis of nanoparticles using bio extracts and their applications in antimicrobial resistance as well as various factors affecting the synthesis process and characterization techniques for ZnO NPs. Recent studies on the antimicrobial activity of biogenic ZnO NPs against different pathogens and their mechanisms of action are discussed. Furthermore, potential applications of biogenic ZnO NPs as antimicrobial agents are highlighted