Novel antimicrobial agents are urgently needed to combat the global threat of antimicrobial resistance. Actinobacteria are remarkable producers of bioactive compounds, which are crucial for the discovery of novel drugs to combat antimicrobial resistance. In the current study, bioactivity, phylogenetic analysis, and a dereplication approach were employed to quickly analyze the metabolomic profiles of selected strains and aid in selection strain prioritization. The aim of this study was to screen Thai actinobacteria isolated from the mangrove ecosystem for antibacterial activities. Taxonomic identification confirmed the classification of these isolates within the genus Streptomyces . Eleven strains identified as Streptomyces yogyakartensis, S. globisporus, S. albiaxialis, S. misionensis, S. iranensis, S. sanyensis, and S. diastaticu s. The crude extracts of the selected actinobacteria strains exhibited antibacterial activities, with minimum inhibitory concentrations ranging from 9.9 to 1250 μg/mL against methicillin‐resistant Staphylococcus aureus , Acinetobacter baumannii , and Klebsiella pneumoniae . Mass‐guided molecular networking analysis of the crude extract revealed the metabolomic complexity of the isolates. Structurally unique compounds such as desferrioxamine E, elaiophylin, kanchanamycin C, bisacuberin, dehydroxynordicadamine, desmethylenylnocardamine, chymostatinol A, chymostatin B, desferrioxamine G, ferrioxamine E, and legonoxamine A were detected in the crude extracts. Notably, we report the potential of bioactive compounds isolated from Thai mangrove actinobacteria, demonstrating diverse biological activities. This study demonstrated the use of metabolomics to annotate putative bioactive compounds, prioritize strains, and discover novel bioactive metabolites.