Supramolecules　have　been　drawing　increasing　attention　recently　in　addressing　healthcare　challenges　caused　by　infectious　pathogens.　We　herein　report　a　novel　class　of　guanidinium-perfunctionalized　polyhedral　oligomeric　silsesquioxane　(Gua-POSS)　supramolecules　with　highly　potent　antimicrobial　activities.　The　modular　structure　of　Gua-POSS　Tm-Cn　consists　of　an　inorganic　T10　or　T8　core　(m　=　10　or　8),　flexible　linear　linkers　of　varying　lengths　(n　=　1　or　3),　and　peripherally　aligned　cationic　guanidinium　groups　as　the　membrane-binding　units.　Such　Gua-POSS　supramolecules　with　spherically　arrayed　guanidinium　cations　display　high　antimicrobial　potency　against　Gram-positive　(Staphylococcus　aureus)　and　Gram-negative　(Escherichia　coli)　bacteria,　as　well　as　fungus　(Candida　albicans),　with　the　best　showing　excellently　low　minimal　inhibitory　concentrations　(MICs)　of　1.7−6.8　μM　in　media,　yet　with　negligible　hemolytic　activity　and　low　in　vitro　cytotoxicity　to　mammalian　cells.　More　significantly,　they　can　inhibit　biofilm　formation　at　around　their　MICs　and　near-completely　break　down　preestablished　difficult-to-break　biofilms　at　250　μg　mL−1　(∼50　μM).　Their　strong　antiviral　efficacy　was　also　experimentally　demonstrated　against　the　enveloped　murine　hepatitis　coronavirus　as　a　surrogate　of　the　SARS-CoV　species.　Overall,　this　study　provides　a　new　design　approach　to　novel　classes　of　sphere-shaped　organic−inorganic　hybrid　supramolecular　materials,　especially　for　potent　antimicrobial,　anti-biofilm,　and　antiviral　applications.　©　2022　American　Chemical　Society.