Hot springs are unique environments where microbial competition drives adaptation and the evolution of potentially novel compounds, making them promising sources for antibiotic discovery. The Roman Baths, with temperatures ranging between 20–42 °C, overlap with the optimal growth conditions of clinically significant ESKAPE pathogens. Actinomycetes inhabiting these ecosystems have evolved competitive strategies to coexist with ESKAPE pathogens, as proved by whole genome shotgun metagenomic sequencing, positioning them as attractive candidates for antibiotic screening. Over 20 actinomycete strains have been isolated from water, sediment, and biofilm samples collected from the Roman Bath hot springs. Application of OSMAC (One Strain Many Active Compounds) strategies, including co-culturing approaches, successfully elicited antimicrobial activity against all ESKAPE pathogens, demonstrating the potential breadth of bioactivity within these isolates. Ongoing efforts focus on optimising culture conditions to maximise antimicrobial production. Whole-genome sequencing of active strains, coupled with secondary screening using reporter assays, is enabling the identification of biosynthetic gene clusters (BGCs) and insights into their potential modes of action. Collectively, these findings highlight Roman Bath actinomycetes as an underexplored and promising reservoir of novel BGCs and bioactive metabolites. Future work aims to extract and characterise organic compounds via mass spectrometry to support future antibiotic development.