Marine microorganisms live in dramatically different environments and have attracted much attention for their structurally unique natural products with potential strong biological activity. Based on the one strain-many compounds (OSMAC) strategy and liquid chromatography mass spectrometry (LC-MS) methods, our continuing efforts on the investigation of novel active compounds from marine Verrucosispora sp. MS100137 has led to the identification of a new polycyclic metabolite, abyssomicin Y (1), together with six known abyssomicin and proximicin analogs (2–7). Abyssomicin Y is a type I abyssomicin with an epoxide group at C-8 and C-9. Compounds 1–3 showed potent inhibitory effects against the influenza A virus; their observed inhibition rates were 97.9%, 98.3%, and 95.9%, respectively, at a concentration of 10 μM, and they displayed lower cytotoxicity than 4. The structures were determined by different NMR techniques and HRMS experiments. This investigation revealed that OSMAC could serve as a useful method for enabling the activation of the silent genes in the microorganism and for the formation of previously unreported active secondary metabolites.