Fungi of the genus Parengyodontium (Ascomycota, Hypocreales, Cordycipitaceae) are emerging as promising sources of secondary metabolites with significant biotechnological potential. While traditionally understudied, species such as Parengyodontium album, Parengyodontium torokii and Parengyodontium americanum have been isolated from diverse and sometimes extreme environments—including deep-sea sediments, mangroves, and NASA clean rooms—suggesting remarkable ecological adaptability. This review presents a comprehensive synthesis of current knowledge on the chemical diversity, biological activities, and potential industrial applications of secondary metabolites produced by fungi belonging this genus. A wide variety of compounds have been identified, including polyketides (e.g., engyodontiumones, alternaphenol B2), terpenoids (e.g., cytochalasin K), alkaloids, and torrubielline derivatives. These metabolites exhibit cytotoxic, antibacterial, and antifouling properties, with promising anticancer and antimicrobial activities. In addition, recent evidence points to the genus’s role in bioremediation, particularly through the degradation of polyethylene by P. album. Despite the advances highlighted here, challenges remain in scaling production, elucidating biosynthetic pathways, and confirming in vivo efficacy. This review underscores the value of integrating chemical, genomic, and metabolomic approaches to fully unlock the biotechnological potential of Parengyodontium species. Additionnally, we broaden the perspective by comparing trends in secondary metabolites among Cordycipitaceae, highlighting lifestyle-related chemical compounds that serve as a reference for the Parengyodontium profile.