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How do cultural biases, trust in government, and perceptions of risk and protective actions influence compliance with regulation of COVID-19? Analyzing Chinese (n = 646) and American public opinion samples (n = 1,325) from spring 2020, we use Grid–Group Cultural Theory and the Protective Action Decision Model to specify, respectively, cultural influences on public risk perceptions and decision-making regarding protective actions. We find that cultural biases mostly affect protective actions indirectly through public perceptions. Regardless of country, hierarchical cultural biases increase protective behaviors via positive perceptions of protective actions. However, other indirect effects of cultural bias via public perceptions vary across both protective actions and countries. Moreover, trust in government only mediates the effect of cultural bias in China and risk perception only mediates the effect of cultural bias in the United States. Our findings suggest that regulators in both countries should craft regulations that are congenial to culturally diverse populations.