“Omics” represent a combinatorial approach to high-throughput analysis of biological entities for various purposes. It broadly encompasses genomics, transcriptomics, proteomics, lipidomics, and metabolomics. Bacteria and microalgae exhibit a wide range of genetic, biochemical and concomitantly, physiological variations owing to their exposure to biotic and abiotic dynamics in their ecosystem conditions. Consequently, optimal conditions for adequate growth and production of useful bacterial or microalgal metabolites are critically unpredictable. Traditional methods employ microbe isolation and ‘blind’-culture optimization with numerous chemical analyses making the bioprospecting process laborious, strenuous, and costly. Advances in the next generation sequencing (NGS) technologies have offered a platform for the pan-genomic analysis of microbes from community and strain downstream to the gene level. Changing conditions in nature or laboratory accompany epigenetic modulation, variation in gene expression, and subsequent biochemical profiles defining an organism’s inherent metabolic repertoire. Proteome and metabolome analysis could further our understanding of the molecular and biochemical attributes of the microbes under research. This review provides an overview of recent studies that have employed omics as a robust, broad-spectrum approach for screening bacteria and microalgae to exploit their potential as sources of drug leads by focusing on their genomes, secondary metabolite biosynthetic pathway genes, transcriptomes, and metabolomes. We also highlight how recent studies have combined molecular biology with analytical chemistry methods, which further underscore the need for advances in bioinformatics and chemoinformatics as vital instruments in the discovery of novel bacterial and microalgal strains as well as new drug leads.