Mangrove ecosystems play essential roles in preventing coastal erosion and serving as nurseries for marine life. Moreover, they have untapped potential in drug discovery, especially from their associated fungi that produce a variety of bioactive compounds belonging to alkaloids, polyketides, and other classes of secondary metabolites. These compounds exhibited promising bioactivities, ranging from anticancer, and anti-infectives to immunosuppressive effects. This chapter examines the specific parts of mangrove plants suitable for obtaining fungal isolates. It provides insights into the ecological interactions between fungi and their host that facilitate the production of bioactive metabolites. Moreover, this chapter covers the chemistry and biological activities of the isolated compounds from mangrove-derived fungi. Particular emphasis is placed on those compounds with remarkable activities and promising further development.