Streptomyces, one of the largest genera belonging to the phylum Actinobacteria, contribute to more than 60% of the clinically relevant antibiotics. The present study outlined the genomics and the metabolomics of a mangrove-derived Streptomyces murinus THV12 strain. The Illumina Hiseq 2500 platform-based whole-genome sequencing of the Streptomyces strain generated a consensus sequence of 8,363,247 bp with 107 contigs and 7345 protein-coding genes, which shared significant homology with genes from Streptomyces murinus. The detection of secondary metabolite biosynthetic gene clusters (smBGCs) in the genome performed using the pipeline antiSMASH v6.1.1 revealed that the strain harbored 47 secondary metabolite clusters, which represented 17.9% of the 8.3 Mb genome. The smBGCs belonged to the metabolite categories: PKS, NRPS, ectoine, lassopeptides, lantipeptides, melanin, siderophores, terpenes and other putative products. The strain showed broad-spectrum antimicrobial activity with a inhibition zone of 30 mm against Gram-positive bacteria and Candida albicans. The secondary metabolite profiling of the crude extracts from the fermentation broth of THV12 was performed with the HPLC system coupled with an Orbitrap Exploris120 high-resolution mass spectrometer. As revealed by in silico analysis, compounds such as actinomycin D, pentamycin, desferrioxamine E and cinnabaramide A were detected with MS/MS analysis. Apart from this, compounds belonging to different chemical scaffolds, such as cyclic and linear peptides, bacterial alkaloids, linear polyketides and terpenoids, were also present in the fermentation broth of the strain when cultivated under the OSMAC (One Strain Many Compounds) approach. Thus, the combined strategy of genome mining and metabolomics of the mangrove-derived strain aided in exploring the chemical diversity of BGCs and new chemical entities, which can contribute to drug leads.