The COVID-19 pandemic disrupted hospital operations. Anecdotal evidence suggests financial performance likewise suffered, yet little empirical research supports this claim. This study aimed to explore the impact of the pandemic on the financial performance of the most prominent academic hospitals in the United States. Data from the 115 largest major teaching hospitals in the United States were extracted from the American Hospital Directory for three years (2019–2021). We hypothesized that the year and region would moderate the relationship between a hospital’s return on assets (financial performance) and specific operational variables. We found evidence through descriptive statistics and multivariate moderated regressions that financial positions rebounded in 2021, mainly through reductions in adjusted full-time employees and liabilities and an increase in non-operating income. Our results also found that the Midwest region significantly outperformed the other three regions, particularly in terms of lower salaries and operational expenses. These findings suggest potential for future initiatives encouraging efficiency and finding alternate sources of income beyond patient income. Hospitals should focus on improving financial reserves, building out non-operational revenue streams, and implementing operational efficiencies to foster better financial resiliency. These suggestions may enable healthcare administrators and facilities to adapt to future pandemics and environmental turbulence.