Coronavirus disease 2019 (COVID-19) exhibits variable symptom severity ranging from asymptomatic to life-threatening, yet the relationship between severity and the humoral immune response is poorly understood. We examined antibody responses in 113 COVID-19 patients and found that severe cases resulting in intubation or death exhibited increased inflammatory markers, lymphopenia, pro-inflammatory cytokines, and high anti-receptor binding domain (RBD) antibody levels. Although anti-RBD immunoglobulin G (IgG) levels generally correlated with neutralization titer, quantitation of neutralization potency revealed that high potency was a predictor of survival. In addition to neutralization of wild-type SARS-CoV-2, patient sera were also able to neutralize the recently emerged SARS-CoV-2 mutant D614G, suggesting cross-protection from reinfection by either strain. However, SARS-CoV-2 sera generally lacked cross-neutralization to a highly homologous pre-emergent bat coronavirus, WIV1-CoV, which has not yet crossed the species barrier. These results highlight the importance of neutralizing humoral immunity on disease progression and the need to develop broadly protective interventions to prevent future coronavirus pandemics. Display omitted •Severe COVID-19 associates with higher antibody production and neutralization titers•Neutralization potency of anti-RBD antibodies predicts disease severity and survival•Immunomodulatory COVID-19-directed therapies modulate antibody responses•COVID-19 sera neutralize D614 and G614 variants, but not pre-emergent WIV1-CoV Garcia-Beltran et al. show that the development of more potent neutralizing antibodies during SARS-CoV-2 infection predicts COVID-19 survival. Protective antibody responses exhibit potent neutralization against the currently circulating SARS-CoV-2 D614G spike variant but lack significant activity against pre-emergent WIV1-CoV spike, suggesting that convalescent patients are likely to remain susceptible to future pandemics.