We urgently need new antimicrobials to treat systemic fungal infections, food and plant pathogens, and bacterial drug resistance. Many bacterial and fungal diseases remain uncontrolled despite research on antibacterial and antifungal agents. Many regions have long used plant and microbial metabolites as therapeutic drugs. Plants contribute 50–60% of these compounds, including alkaloids, flavonoids, steroids, terpenoids, and polysaccharides, while microbial metabolites contribute 5%. The vast unexplored diversity of microorganisms may yield novel and bioactive metabolites. Thus, research is increasingly focused on rare and understudied microorganisms from diverse ecological habitats. Endolichenic fungi live in lichen thalli with algae. They are similar to plant endophytes, which live inside the cells of their host plants. Several antibiotics and natural bioactive compounds with multiple uses have developed them. According to the WHO, a large percentage of developing countries' populations rely on local medicinal products for primary health care, driving up demand for medicinal plants worldwide. Plants' ability to synthesize antimicrobial potency compounds (secondary metabolites) helps fight antibiotic resistance. We reviewed these organisms' potential as sources of novel antimicrobial compounds. These fungi may produce bioactive substances that fight harmful microorganisms. Understanding their antimicrobial properties could lead to new antibiotics that address antibiotic resistance. This research is essential for finding alternative treatments and understanding natural antimicrobials.