In this study, a marine brown alga -derived fungal strain, SC29, was isolated and identified. Column chromatography of the extracts from liquid fermented products of the fungal strain was carried out and led to the isolation of six compounds. Their structures were elucidated by spectroscopic analysis and supported by single-crystal X-ray diffraction as four previously undescribed ( )-3-hydroxybutyric acid and glycolic acid derivatives, namely penisterines A ( ) and C-E ( - ) and penisterine A methyl ether ( ), isolated for the first time from natural resources, along with ( )-3-hydroxybutyric acid ( ). Of these compounds identified, penisterine E ( ) was a unique 6/6/6-tricyclic ether with an acetal and two hemiketal functionalities. All the isolates were subjected to in vitro anti-angiogenic assays using a human endothelial progenitor cell (EPCs) platform. Among these, penisterine D ( ) inhibited EPC growth, migration, and tube formation without any cytotoxic effect. Further, in in vivo bioassays, the percentages of angiogenesis of compound on ( :EGFP) transgenic zebrafish were 54% and 37% as the treated concentration increased from 10.2 to 20.4 µg/mL, respectively, and the percentages of angiogenesis of compound were 52% and 41% as the treated concentration increased from 8.6 to 17.2 µg/mL, respectively. The anti-angiogenic activity of penisterine D ( ) makes it an attractive candidate for further preclinical investigation.