We used the recombinant trimeric spike (S) glycoprotein in the prefusion conformation to immunize horses for the production of hyperimmune globulins against SARS-CoV-2. Serum antibody titers measured by ELISA were above 1:10⁶, and the neutralizing antibody titer against authentic virus (WT) was 1:14,604 (average PRNT₉₀). Plasma from immunized animals was pepsin digested to remove the Fc portion and purified, yielding an F(ab’)₂ preparation with PRNT₉₀ titers 150-fold higher than the neutralizing titers in human convalescent plasma. Challenge studies were carried out in hamsters and showed the in vivo ability of equine F(ab’)₂ to reduce viral load in the pulmonary tissues and significant clinical improvement determined by weight gain. The neutralization curve by F(ab’)₂ was similar against the WT and P.2 variants, but displaced to higher concentrations by 0.39 log units against the P.1 (Gamma) variant. These results support the possibility of using equine F(ab’)₂ preparation for the clinical treatment of COVID patients.