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Abstract Antivirals that can combat coronaviruses, including SARS‐CoV‐2 and associated mutants, are urgently needed but lacking. Simultaneously targeting the viral physical structure and replication cycle can endow antivirals with sustainable and broad‐spectrum anti‐coronavirus efficacy, which is difficult to achieve using a single small‐molecule antiviral. Thus, a library of nanomaterials on GX_P2V, a SARS‐CoV‐2‐like coronavirus of pangolin origin, is screened and a surface‐functionalized gold nanocluster (TMA‐GNC) is identified as the top hit. TMA‐GNC inhibits transcription‐ and replication‐competent SARS‐CoV‐2 virus‐like particles and all tested pseudoviruses of SARS‐CoV‐2 variants. TMA‐GNC prevents viral dissemination through destroying membrane integrity physically to enable a virucidal effect, interfering with viral replication by inactivating 3CL protease and priming the innate immune system against coronavirus infection. TMA‐GNC exhibits biocompatibility and significantly reduces viral titers, inflammation, and pathological injury in lungs and tracheas of GX_P2V‐infected hamsters. TMA‐GNC may have a role in controlling the COVID‐19 pandemic and inhibiting future emerging coronaviruses or variants.