Non-pharmaceutical interventions (NPIs), which were governments’ primary tools to mitigate SARS-CoV-2 transmission prior to the arrival of COVID-19 vaccines and antiviral treatments, necessitated a trade-off between the health impacts of viral spread and the social and economic costs of restrictions. We develop a statistical decision framework and conduct a cost-effectiveness analysis of NPI policies enacted at the state level in the United States in 2020. Although school closures reduced viral transmission, their social impact in terms of student learning loss was too costly. Conditional on the other policies enacted, extended school closures imposed a cost to the nation’s youth in service of its older generations, reducing the latter’s risk of death at the expense of $2 trillion (USD2020) in future GDP. Moreover, we find that this marginal trade-off between school closure and COVID deaths was not inescapable: more timely, stringent, and enduring use of other measures would have sufficed to maintain similar or lower mortality rates without incurring profound learning loss. Optimal NPI policies involve consistent implementation of mask mandates, public test availability, contact tracing, social distancing orders, and reactive workplace closures, with no closure of schools beyond the usual 16 weeks of break per year. Their use would have reduced the gross impact of the pandemic in the U.S. in 2020 from $4.6 trillion to $1.9 trillion and, with high probability, saved over 100,000 lives.