Extremophiles span through all taxonomic ranges starting from prokaryotes to Eucarya as well as Archaea. Extremophiles are categorized into seven groups on the basis of their various extreme habitats. Piezophiles withstand high hydrostatic pressure and reside at deep-sea sediments or are isolated from the bottom-dwelling animals’ guts. Piezophilic fungi are known to produce plethora of natural compounds with tremendous preclinical and clinical significance. Deep-sea-derived fungi such as different strains of Phialocephala sp., Penicillium sp., Ascomycota sp., Aspergillus sp., and Emericella sp. have been known to produce an array of pharmacologically active compounds such as diketopiperazine and oxindole alkaloids, sorbicillin-type compounds, diterpenes like brevianespiroditerpenoids, prenylxanthones, hydroxyphenyl acetic acid, etc. exhibiting antimicrobial, antiviral, anticancer, a-glucosidase inhibitory, and antioxidant properties in a number of preclinical investigations. The present review comprehensively retrieves the reports on novel piezophilic fungi-derived natural products mainly focusing on the recent literature emphasizing on their structures, biological activities, and structure-activity analyses with a note on future clinical implications of such piezophiles-derived drugs. © The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2022.