Microbial pathogens that cause severe infections and are resistant to drugs are simultaneously becoming more active. This urgently calls for novel effective antibiotics. Organisms from extreme environments are known to synthesize novel bioprospecting molecules for biomedical applications due to their peculiar characteristics of growth and physiological conditions. Antimicrobial developments from hypersaline environments, such as lagoons, estuaries, and salterns, accommodate several halophilic microbes. Salinity is a distinctive environmental factor that continuously promotes the metabolic adaptation and flexibility of halophilic microbes for their survival at minimum nutritional requirements. A genetic adaptation to extreme solar radiation, ionic strength, and desiccation makes them promising candidates for drug discovery. More microbiota identified via sequencing and ‘omics’ approaches signify the hypersaline environments where compounds are produced. Microbial genera such as Bacillus, Actinobacteria, Halorubrum and Aspergillus are producing a substantial number of antimicrobial compounds. Several strategies were applied for producing novel antimicrobials from halophiles including a consortia approach. Promising results indicate that halophilic microbes can be utilised as prolific sources of bioactive metabolites with pharmaceutical potentialto expand natural product research towards diverse phylogenetic microbial groups which inhabit salterns. The present study reviews interesting antimicrobial compounds retrieved from microbial sources of various saltern environments, with a discussion of their potency in providing novel drugs against clinically drug-resistant microbes.