In this study, Burgess et al. show that replication of SARS-CoV-2, the agent responsible for the COVID-19 pandemic, and a seasonal human β-coronavirus, HCoV-OC43, can be suppressed by depletion of nuclear RNA methyltransferase METTL3 or cytoplasmic m6A reader proteins YTHDF1 and YTHDF3 and by a highly specific small molecule METTL3 inhibitor. Their findings establish that coronavirus RNAs are m6A-modified and host m6A pathway components control β-coronavirus replication, and illustrate the therapeutic potential of inhibiting METTL3 to restrict coronavirus reproduction.