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Immunization with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike elicits diverse antibodies, but it is unclear if any of the antibodies can neutralize broadly against other beta-coronaviruses. Here, we report antibody WS6 from a mouse immunized with mRNA encoding the SARS-CoV-2 spike. WS6 bound diverse beta-coronavirus spikes and neutralized SARS-CoV-2 variants, SARS-CoV, and related sarbecoviruses. Epitope mapping revealed WS6 to target a region in the S2 subunit, which was conserved among SARS-CoV-2, Middle East respiratory syndrome (MERS)-CoV, and hCoV-OC43. The crystal structure at 2 Å resolution of WS6 revealed recognition to center on a conserved S2 helix, which was occluded in both pre- and post-fusion spike conformations. Structural and neutralization analyses indicated WS6 to neutralize by inhibiting fusion and post-viral attachment. Comparison of WS6 with other recently identified antibodies that broadly neutralize beta-coronaviruses indicated a stem-helical supersite—centered on hydrophobic residues Phe1148, Leu1152, Tyr1155, and Phe1156—to be a promising target for vaccine design. [Display omitted] • Antibody WS6 from SARS-CoV-2 spike-immunized mice binds diverse beta-CoV spikes • WS6 neutralizes SARS-CoV-2 variants, SARS-CoV, and related sarbecoviruses • Crystal structure of WS6 with a conserved S2 peptide reveals a helical epitope • WS6 epitope belongs to an S2 supersite recognized by diverse antibodies Shi et al. identified a broad beta-coronavirus neutralizing antibody from mice immunized with mRNA encoding the SARS-CoV-2 spike. This antibody targets an S2 supersite comprising a hydrophobic cluster spanning three helical turns, which are conserved among beta-coronaviruses. This S2 supersite appears to be a good target for broad beta-coronavirus vaccines. [ABSTRACT FROM AUTHOR]