Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and related human coronaviruses (hCoVs) regulate host gene expression to facilitate viral replication and evade innate immunity. SARS-CoV-2 nonstructural protein 1 (Nsp1) suppresses host gene expression in part by inhibiting cellular mRNA nuclear export through targeting the mRNA export factor NXF1. However, whether this mechanism is conserved among Nsp1 proteins from diverse hCoVs remains unknown. Here, we demonstrate that Nsp1 proteins from SARS-CoV, SARS-CoV-2, and MERS-CoV, but not those from endemic hCoVs, induce pronounced nuclear accumulation of host poly(A) RNA without altering global transcript levels. Nsp1 proteins from these highly pathogenic hCoVs directly interact with NXF1, whereas endemic hCoV Nsp1 proteins show little or no detectable NXF1 interaction. Structural modeling and mutagenesis identify a conserved N-terminal acidic patch in Nsp1 that contacts the basic surface of the NXF1 RNA recognition motif. Disruption of this interface abolishes the Nsp1-NXF1 interaction and restores host mRNA export while preserving NXF1 interactions with core mRNA export factors. Together, our findings define a conserved structural mechanism by which highly pathogenic hCoV Nsp1 targets NXF1 to inhibit host mRNA export and provide a potential framework for broad-spectrum antiviral intervention.