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Abstract Microbial‐derived natural products remain a major source of structurally diverse bioactive compounds and chemical scaffolds that have the potential as new therapeutics to target drug‐resistant pathogens and cancers. In particular, genome mining has revealed the vast number of cryptic or low‐yield biosynthetic gene clusters in the genusStreptomyces. However, low natural product yields—improvements to which have been hindered by the lack of high throughput methods—have slowed the discovery and development of many potential therapeutics. Here, we describe our efforts to improve yields of landomycins—angucycline family polyketides under investigation as cancer therapeutics—by a genetically modifiedStreptomyces cyanogenus136. After simplifying the extraction process fromS. cyanogenuscultures, we identified a wavelength at which the major landomycin products are absorbed in culture extracts, which we used to systematically explore culture medium compositions to improve total landomycin titers. Through correlational analysis, we simplified the culture optimization process by identifying an alternative wavelength at which culture supernatants absorb yet is representative of total landomycin titers. Using the subsequently improved sample throughput, we explored landomycin production during the culturing process to further increase landomycin yield and reduce culture time. Testing the antimicrobial activity of the isolated landomycins, we report broad inhibition of Gram‐positive bacteria, inhibition of fungi by landomycinone, and broad landomycin resistance by Gram‐negative bacteria that is likely mediated by the exclusion of landomycins by the bacterial membrane. Finally, the anticancer activity of the isolated landomycins against A549 lung carcinoma cells agrees with previous reports on other cell lines that glycan chain length correlates with activity. Given the prevalence of natural products produced byStreptomyces, as well as the light‐absorbing moieties common to bioactive natural products and their metabolic precursors, our method is relevant to improving the yields of other natural products of interest.