In recent decades, technological advantages have allowed scientists to isolate medicinal compounds from marine organisms that exhibit unique structure and bioactivity. The mangrove fungus Xylaria sp. from the South China Sea is rich in metabolites and a potent therapeutic compound, xyloketal B, has been isolated in 2001. Since then, xyloketal B has been extensively studied in a wide variety of cell types and in vitro and in vivo disease models. Xyloketal B and its derivatives exhibit cytoprotective effects in cardiovascular and neurodegenerative diseases by reducing oxidative stress, regulating the apoptosis pathway, maintaining ionic balance, mitigating inflammatory responses, and preventing protein aggregation. Xyloketal B has also shown to alleviate lipid accumulation in a non-alcoholic fatty liver disease model. Moreover, xyloketal B treatment induces glioblastoma cell death. This review summarizes our current understanding of xyloketal B in various disease models.