Stemming on the theoretical framework of individualism-collectivism, this study aims to interpret COVID-19 prevention behaviors in young adults in the light of cultural orientations, hypothesizing the mediating role of two pandemic affects (i.e., fear for COVID-19 consequences and psychological distress during pandemic). Participants were 296 young adults living in Italy ( = 23.96, = 3.04; 79.7% women), who completed an online anonymous survey. Data were gathered from December 2020 to May 2021. A path analysis model explored direct and indirect relationships among study variables. Psychological distress significantly reduced the compliance with prevention measures, whereas pandemic fears increased it. The collectivistic orientations (Vertical Collectivism and Horizontal Collectivism) positively predicted prevention behaviors increasing pandemic fears. The egalitarian dimensions (Horizontal Individualism and Horizontal Collectivism) were positive predictors of compliance reducing psychological distress during pandemic. Finally, Vertical Individualism was a risk factor that negatively predicted prevention behaviors both directly and indirectly, increasing psychological distress. The results provide new insights into the emotional mechanisms that link individualism and collectivism orientations to COVID-19 prevention behaviors, with interesting implications for public health policies, prevention, and future research.