<p>The rapid rise in antibiotic resistance, which causes more than 700,000 deaths worldwide each year, has intensified the search for alternative antimicrobial sources to combat multidrug-resistant (MDR) pathogens. Halophilic microorganisms inhabiting hypersaline environments represent underexplored reservoirs of structurally diverse bioactive metabolites. Halophiles rely on distinctive osmoadaptation strategies, such as “salt-in” and “salt-out” mechanisms, that contribute to the structural stability and functional resilience of their metabolites under conditions that may compromise the efficacy of conventional antibiotics. Several halophile-derived compounds exhibit non-classical antimicrobial mechanisms, including membrane destabilization, disruption of ion homeostasis, and interference with quorum sensing. These multi-target strategies may reduce susceptibility to common resistance mechanisms such as efflux activity and enzymatic inactivation. However, most reported compounds remain at the in vitro stage, with limited progression to in vivo validation. Integrating synthetic biology, metabolic engineering, and multi-omics approaches may facilitate activation of silent biosynthetic pathways and improve translational feasibility. This review integrates ecological adaptations, mechanistic insights into antimicrobial mechanisms, and modern omics-driven and computational discovery pipelines into a unified framework for antimicrobial discovery.</p> Graphical Abstract <p></p>