Microbial resources are diverse and abundant, serving as a crucial source for the discovery of bioactive substances. However, as the research on microbial secondary metabolites deepens, discovering new microorganisms and novel bioactive secondary metabolites from conventional environments is becoming increasingly challenging. The microorganisms inhabiting extreme environments have unique physiological characteristics and can develop distinctive metabolic pathways, holding immense potential for producing chemically diverse and novel bioactive secondary metabolites. This article comprehensively overviews the recent advancements in the isolation strategies of microorganisms from extreme environments and the research progress in their bioactive substances, including antimicrobial, anticancer, and antioxidant compounds. This review aims to serve as a reference for the development and utilization and the related studies of the microbial resources in extreme environments.