New metabolites, xiamycins C-E (1-3), were isolated from a Streptomyces. sp (#HK18) culture inhabiting the topsoil in a Korean solar saltern. The planar structures of the xiamycins C-E were elucidated as carbazole-bearing indolosesquiterpenoids using a combined analysis of NMR, MS, UV, and IR spectroscopic data. The absolute configurations of these new compounds were determined by analyses of NOESY and ECD data. When the xiamycins were tested for inhibitory activity on porcine epidemic diarrhea virus (PEDV), xiamycin D (2) showed the strongest inhibitory effect on PEDV replication (EC50 = 0.93 μM) with low cytotoxicity (CC50 = 56.03 μM), thus displaying a high selective index (60.31). Quantitative real-time PCR data revealed the inhibitory effect of 2 on genes encoding essential structural proteins (GP6 nucleocapsid, GP2 spike, and GP5 membrane) for PEDV replication in a dose-dependent manner. The antiviral activity of xiamycin D (2) was also supported by both Western blotting of the GP2 spike and GP6 nucleocapsid protein synthesis of PEDV. Therefore, xiamycin D shows the potential of indolosesquiterpenoids as new and promising chemical skeletons against PEDV-related viruses.