Lichens are formed through a mutualistic interaction between one main fungal species, known as the mycobiont, and algae and/or cyanobacteria species, known as the photobionts. Lichens, particularly the mycobiont component, are known to produce various secondary metabolites which have distinct physiological roles in order to protect from biotic and abiotic stress. This review explores the antimicrobial potential of lichen-derived secondary metabolites, highlighting their efficacy against a variety of microorganisms. Based on a exhaustive analysis of the scientific literature, we discuss the mechanisms of action and potential applications of these metabolites in the fight against antibiotic resistance and emerging infectious diseases. Lichen-derived compounds, such as diffractaic, lobaric, protolichesterinic, salazinic and usnic acid, exhibit diverse antimicrobial properties, demonstrating activity against a wide range of bacteria, fungi and yeasts, often with significant minimal inhibitory concentrations (MICs). Some of them also show promise as antiviral agents. In addition, certain metabolites show synergism with conventional antibiotics, which could enhance their efficacy. Finally, the interaction of molecules present in culture supernatants of lichens and inorganic ions, in the form of nanoparticles, presenting antimicrobial activity, is also described. This literature review highlights the therapeutic potential of lichen metabolites in the fight against various microbial infections, making them valuable targets for future research and drug development. Keywords: Antibacterial; Antifungal; Antiviral; Photobiont; Mycobiont; Holobiont.