Background Currently, there is limited research on the prognostic value of NT‐proBNP (N‐terminal pro‐B‐type natriuretic peptide) as a biomarker in COVID‐19. We proposed the a priori hypothesis that an elevated NT‐proBNP concentration at admission is associated with increased in‐hospital mortality. Methods and Results In this prospective, observational cohort study of the American Heart Association’s COVID‐19 Cardiovascular Disease Registry, 4675 patients hospitalized with COVID‐19 were divided into normal and elevated NT‐proBNP cohorts by standard age‐adjusted heart failure thresholds, as well as separated by quintiles. Patients with elevated NT‐proBNP (n=1344; 28.7%) were older, with more cardiovascular risk factors, and had a significantly higher rate of in‐hospital mortality (37% versus 16%; P <0.001) and shorter median time to death (7 versus 9 days; P <0.001) than those with normal values. Analysis by quintile of NT‐proBNP revealed a steep graded relationship with mortality (7.1%–40.2%; P <0.001). NT‐proBNP was also associated with major adverse cardiac events, intensive care unit admission, intubation, shock, and cardiac arrest ( P <0.001 for each). In subgroup analyses, NT‐proBNP, but not prior heart failure, was associated with increased risk of in‐hospital mortality. Adjusting for cardiovascular risk factors with presenting vital signs, an elevated NT‐proBNP was associated with 2‐fold higher adjusted odds of death (adjusted odds ratio [OR], 2.23; 95% CI, 1.80–2.76), and the log‐transformed NT‐proBNP with other biomarkers projected a 21% increased risk of death for each 2‐fold increase (adjusted OR, 1.21; 95% CI, 1.08–1.34). Conclusions Elevated NT‐proBNP levels on admission for COVID‐19 are associated with an increased risk of in‐hospital mortality and other complications in patients with and without heart failure.