A new nonribosomal peptide, nyuzenamide C (<b>1</b>), was discovered from riverine sediment-derived <i>Streptomyces</i> sp. DM14. Comprehensive analysis of the spectroscopic data of nyuzenamide C (<b>1</b>) revealed that <b>1</b> has a bicyclic backbone composed of six common amino acid residues (Asn, Leu, Pro, Gly, Val, and Thr) and four nonproteinogenic amino acid units, including hydroxyglycine, β-hydroxyphenylalanine, <i>p</i>-hydroxyphenylglycine, and 3,β-dihydroxytyrosine, along with 1,2-epoxypropyl cinnamic acid. The absolute configuration of <b>1</b> was proposed by <i>J</i>-based configuration analysis, the advanced Marfey's method, quantum mechanics-based DP4 calculations, and bioinformatic analysis of its nonribosomal peptide synthetase biosynthetic gene cluster. Nyuzenamide C (<b>1</b>) displayed antiangiogenic activity in human umbilical vein endothelial cells and induced quinone reductase in murine Hepa-1c1c7 cells.