In this study, we analyze the complexity of COVID-19 policies that must balance public health and economic outcomes by adopting a configurational perspective. Through a fuzzy-set qualitative comparative analysis (fsQCA), we reveal multiple, nonlinear combinations of the policies leading to the success and failure of health and economic outcomes, using 1543 cases built from a variety of sources. The results provide policymakers with a complementary and substitutive multiple-policy strategy in navigating a complex, unstable environment. Our analysis reveals several noteworthy findings. Each of the four outcomes can be achieved through different pathways. For instance, three configurations lead to Low COVID-19 Deaths, one suggesting an all-in approach with the presence of all causal conditions while an alternative pathway suggesting a combination of present and absent conditions. Further, we note that the causal-effect relation is asymmetric, e.g., school closures can lead to both Low and High COVID-19 Death outcomes, depending on both demand and supply policies undertaken. We provide valuable guidance to policymakers on the need to protect lives with the need to protect livelihoods, an ethical dilemma beyond health crisis settings. Our study framework applies to many policy decisions that involve weighing the protection of human life against economic loss. •Executive Takeaways.•A configurational analysis of COVID-19 policies balances public health and economic outcomes.•It provides policymakers with complementary and substitutive strategies.•It reveals a cause/effect relationship that is conjunctional, equifinal, and asymmetric.•Results inform a policy matrix for mitigating the ethical dilemma of protecting both lives and livelihoods.