A human neutralizing antibody, CB6, was isolated from a patient recovering from COVID-19 and shown to effectively neutralize SARS-CoV-2. The antibody targets the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein, overlapping with the ACE2-binding site, thereby blocking virus-receptor interactions through steric hindrance and direct competition. CB6 demonstrated potent neutralizing activity in vitro, inhibiting SARS-CoV-2 infection in both pseudovirus and live virus assays. In a rhesus macaque model, CB6 reduced viral load and alleviated lung damage when administered prophylactically or therapeutically. Structural analysis revealed that CB6 binds to the RBD with a buried surface area of 1,088 Ų, and its binding overlaps with the ACE2-binding site, suggesting resistance to mutations. CB6 was also found to be safe, with LALA mutations in the Fc region preventing antibody-dependent enhancement. The study highlights CB6 as a promising candidate for clinical translation in the treatment of COVID-19.A human neutralizing antibody, CB6, was isolated from a patient recovering from COVID-19 and shown to effectively neutralize SARS-CoV-2. The antibody targets the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein, overlapping with the ACE2-binding site, thereby blocking virus-receptor interactions through steric hindrance and direct competition. CB6 demonstrated potent neutralizing activity in vitro, inhibiting SARS-CoV-2 infection in both pseudovirus and live virus assays. In a rhesus macaque model, CB6 reduced viral load and alleviated lung damage when administered prophylactically or therapeutically. Structural analysis revealed that CB6 binds to the RBD with a buried surface area of 1,088 Ų, and its binding overlaps with the ACE2-binding site, suggesting resistance to mutations. CB6 was also found to be safe, with LALA mutations in the Fc region preventing antibody-dependent enhancement. The study highlights CB6 as a promising candidate for clinical translation in the treatment of COVID-19.