<jats:title>Abstract</jats:title><jats:p>The cancer‐cell‐cytotoxicity‐guided fractionation of the acetone extracts of two cultured marine‐derived <jats:italic>Streptomyces</jats:italic> strains belonging to the MAR4 group yielded six new napyradiomycins, compounds A–F (<jats:bold>1</jats:bold>–<jats:bold>6</jats:bold>), together with three known compounds, napyradiomycins B2–B4 (<jats:bold>7</jats:bold>–<jats:bold>9</jats:bold>). Napyradiomycins <jats:bold>1</jats:bold>–<jats:bold>4</jats:bold> are new members of the napyradiomycin “C‐type” meroterpenoids, which possess a linear monoterpene bridge between C‐7 and C‐10a. Compound <jats:bold>4</jats:bold> has an additional tetrahydropyran ring fused to the phenol moiety. Compounds <jats:bold>5</jats:bold>–<jats:bold>9</jats:bold> are related to the napyradiomycin “B‐type” meroterpenoids. The structures of all new compounds were assigned by interpretation of 1D and 2D NMR, MS, and other spectroscopic data. The relative configurations were assigned based upon interpretation of ROESY 2D NMR experiments. The cytotoxicity of <jats:bold>1</jats:bold>–<jats:bold>9</jats:bold> against the human colon carcinoma cell line HCT‐116 and their antibacterial activities against methicillin‐resistant <jats:italic>Staphylococcus aureus</jats:italic> (MRSA) are presented.